Pyrrolopyridazine derivatives

ABSTRACT

The invention relates to compound of the formula (I) or its salt, in which R 1 , R 2 , R 3  and R 4  are as defined in the description, their use of as medicament, the process for their preparation and use for the treatment of PDE-IV or TNF-α mediated diseases.

TECHNICAL FIELD

This invention relates to new pyrrolopyridazine derivatives andpharmaceutically acceptable salts thereof which inhibit enzymaticactivity of phosphodiesterase IV (PDE IV) and production of tumornecrosis factor-α (TNF-α).

BACKGROUND ART

Cyclic adenosine monophosphate (adenosine 3′,5′-cyclic monophosphate,“cAMP” or “cyclic AMP”) is known as an intracellular second messenger,which is intermediated by a first messenger (hormone, neurotransmitteror autacoid) and the cellar responses. The first messenger stimulatesthe enzyme responsible for synthesis of cAMP, and then the cAMPintervenes in many functions such as metabolic, contractile orsecretory. The effect of cAMP end when it is degraded by cyclicnucleotide phosphodiesterases, in particular phosphosiesterase-4 (PDE4or PDE-IV), which is specific for cAMP. PDE-IV have been identified inmany tissues including the central nervous systems, the heart, vascularsmooth muscle, airway smooth muscle, myeloid lines, lymphoid, and thelike. Evaluation of cAMP level by using the PDE-IV inhibitor wouldproduce beneficial effect on inappropriate activation of airway smoothmuscle and a wide variety of inflammatory cells.

A major concern with the use of PDE-IV inhibitors is the side effect ofemesis which has been observed for several candidate compounds asdescribed in C. Burnouf et al., (Ann. Rep. In Med. Chem.,33:91-109(1998)). Burnouf describe the wide variation of the severity ofthe undesirable side effects exhibited by various compounds.

Some condensed heterocyclic derivatives having the inhibitory activityof PDE-IV have been known, for example in WO0.3/016279, WO0.3/018579,WO0.3/000679 and the like. However, there remains a need for novelcompounds that inhibit PDE-TV with minimal side effects. Although somepyrrolopyridazine derivatives having the inhibitory activity ofhydroxymethylglutaryl (HMG) CoA reductase have been known, for example,in WO91/18903, pyrrolopyridazine derivatives having the inhibitoryactivity of PDE-IV have not been known.

DISCLOSURE OF INVENTION

This invention relates to new pyrrolopyridazine derivatives.

The compounds of this invention inhibit cAMP phosphodiesterase enzymes,in particular phosphodiesterase-4 enzyme, and also inhibit theproduction of tumor necrosis factor-α (TNF-α), a serum glycoprotein.

Accordingly, one object of this invention is to provide the new anduseful pyrrolopyridazine derivatives and pharmaceutically acceptablesalts thereof which possess a strong phosphodiesterase-4 (PDEIV)-inhibitory activity and a strong inhibitory activity on theproduction of tumor necrosis factor (TNF).

Another object of this invention is to provide processes for preparationof the pyrrolopyridazine derivatives and salts thereof.

A further object of this invention is to provide a pharmaceuticalcomposition comprising said pyrrolopyridazine derivatives or apharmaceutically acceptable salt thereof.

Still further object of this invention is to provide a use of saidpyrrolopyridazine derivatives or a pharmaceutically acceptable saltthereof as a medicament for prophylactic and therapeutic treatment ofPDE-IV and TNF mediated diseases such as chronic inflammatory diseases,specific autoimmune diseases, sepsis-induced organ injury, and the likein human being and animals.

The object pyrrolopyridazine derivatives of the present invention arenovel and can be represented by the following general formula (I):

in which

-   R¹ is (1) carboxy or protected carboxy,    -   (2) —CONR⁵R⁶,    -   (3) hydroxy or lower alkoxy,    -   (4) amino, cyclo(lower)alkylamino or mono- or        di(lower)alkylamino optionally substituted by lower alkoxy,    -   (5) trihalo(lower)alkyl,    -   (6) trihalo(lower)alkylsulfonyloxy or arylsulfonylamino,    -   (7) substituted or unsubstituted lower alkyl,    -   (8) substituted or unsubstituted aryl, or    -   (9) substituted or unsubstituted heterocyclic group,-   R² is R⁷ or —(A¹)p-X-A²-R⁷,    -   wherein    -   p is integer of 0 or 1;    -   A¹ is (C₁-C₂)alkylene or —CH═CH—;    -   A² is —(C₁-C₂)n- or —(CH═CH)m- [wherein n is integer which may        range from 1 to 6 and m is integer which may range from 1 to 3];    -   X is single bond, —O—, —NR⁸—, —C(═O)—, —C(═NR⁹)— or        hydroxy(C₁-C₂)alkylene [wherein R⁸ is hydrogen or lower alkyl,        and R⁹ is substituted or unsubstituted N-containing heterocyclic        group]; and    -   R⁷ is    -   (1) hydrogen,    -   (2) substituted or unsubstituted aryl,    -   (3) substituted or unsubstituted heterocyclic group,    -   (4) carboxy, protected carboxy or CONR¹⁰R¹¹,    -   (5) acyl or halocarbonyl,    -   (6) cyano,    -   (7) amino, protected amino, or mono- or di(lower)alkylamino,    -   (8) hydroxy, aryloxy, acyloxy or lower alkoxy optionally        substituted by hydroxy or acyloxy,    -   (9) lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl,        or    -   (10) —O—R¹²,    -   or-   R¹ and R² are combined together to form lower alkylene or lower    alkenylen group, which is optionally interrupted by amino or    sulfonyl and optionally fuse with benzene ring, and also is    optionally substituted by the group consisting of lower alkyl,    hydroxy, oxo and lower alkoxy,-   R³ is substituted or unsubstituted aryl, or substituted or    unsubstituted heterocyclic group,-   R⁴ is hydrogen, halogen, cyano, carbamoyl, acyl, thiocyanate, lower    alkylthio, lower alkenyl, hydroxyl(lower)alkyl, trihalo(lower)alkyl    or lower alkyl,-   R⁵, R⁶, R¹⁰ and R¹¹ each independently represents hydrogen, lower    alkylsulfonyl, heterocyclic group or lower alkyl optionally    substituted by hydroxy, alkoxy, sulfo, carboxy, protected carboxy or    —R¹⁷,    -   or alternatively R⁵ and R⁶ or R¹⁰ and R¹¹, together with the        nitrogen atom to which they are attached, represent N-containing        heterocyclic group, and-   R¹² and R¹⁷ are each independently a group derived from protected or    unprotected sugar by removal of the hydroxy group therefrom,    or a pharmaceutically acceptable salt thereof, or prodrug thereof.

Suitable pharmaceutically acceptable salts of the object compound (I)are conventional non-toxic salts and may include a salt with a base oran acid addition salt such as a salt with an inorganic base, forexample, an alkali metal salt (e.g., sodium salt, potassium salt, etc.),an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.),an ammonium salt; a salt with an organic base, for example, an organicamine salt (e.g., triethylamine salt, pyridine salt, picoline salt,ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt, etc.); an inorganic acid additionsalt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); anorganic carboxylic or sulfonic acid addition salt (e.g., formate,acetate, trifluoroacetate, maleate, tartrate, fumarate,methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt witha basic or acidic amino acid (e.g., arginine, aspartic acid, glutamicacid, etc.).

The “prodrug” means the derivatives of the object compound (I) having achemically or metabolically degradable group, which becamepharmaceutically active after chemo- or biotransformation.

Preferred embodiments of the object compound (I) are as follows.

in which

-   R¹ is (1) carboxy or esterified carboxy (more preferably,    ethoxycarbonyl),    -   (2) —CONR⁵R⁶ [wherein R⁵ and R⁶ each independently represents        lower alkyl, or alternatively R⁵ and R⁶, together with nitrogen        atom to which they are attached represents saturated 5- or        6-membered heteromonocyclic group containing 1 to 2 nitrogen        atom(s).] (more preferably, dimethylcarbamoyl or        1-pyrrolidinylcarbonyl),    -   (3) hydroxy or lower alkoxy,    -   (4) amino, cyclo(lower)alkylamino, or mono- or        di(lower)alkylamino optionally substituted by lower alkoxy,    -   (5) trihalo(lower)alkyl,    -   (6) trihalo(lower)alkylsulfonyloxy or arylsulfonylamino,    -   (7) lower alkyl optionally substituted by (i) halogen; (ii)        carboxy; (iii) protected carboxy; (iv) cyano; (v)        carbamoyl; (vi) —OCONR¹⁵R¹⁶ [wherein R¹⁵ and R¹⁶ each        independently represents hydrogen, aryl or lower alkyl        optionally substituted by aryl, or R¹⁵ and R¹⁶, together with        the nitrogen atom to which they are attached, represents        saturated 5- or 6-membered heteromonocyclic group containing 1        to 2 nitrogen atom(s) and also optionally containing oxygen        atom.] (more preferably, dimethylcarbamoyloxy,        methyl-phenylcarbamoyloxy, morpholinylcarbonyloxy or        pyrrolidinylcarnbonyloxy); (vii) lower alkylthio; (viii) lower        alkylsulfonyl; (ix) lower alkylsulfonyloxy; (x) lower        alkylsulfonylamino; (xi) mono- or di(lower)alkylamino optionally        substituted by hydroxy, lower alkoxy, aryloxy, or substituted or        unsubstituted aryl; (xii) amino; (xiii) acylamino (more        preferably, lower alkanoylamino such as acetylamino, aroylamino        such as benzoylamino, or heterocycliccarbonylamino such as        pyrazinylcarbonylamino); (xiv) protected amino such as        phthalimide, benzylamino or lower alkoxycarbonylamino; (xv)        hydorxy; (xvi) acyloxy (more preferably, lower alkanoyloxy such        as acetyloxy); (xvii) cyclo(lower)alkyloxy; (xviii)        aryloxy; (xix) substituted or unsubstituted aryl (more        preferably, phenyl); (xx) saturated or unsaturated 5- or        6-membered heteromonocyclic group containing 1 to 3 nitrogen        atom(s) and also optionally containing oxygen atom or sulfur        atom (more preferably, piperazinyl, morpholinyl, oxazolidinyl,        thiomorpholinyl, piperidinyl, pyrrolidinyl or triazolyl)        optionally substituted by lower alkyl, hydroxy(lower)alkyl, aryl        or oxo; or (xxi) lower alkoxy optionally substituted by carboxy,        protected carboxy, hydroxy, protected hydroxy, lower alkoxy,        cyclo(lower)alkyl, substituted or unsubstituted aryl (more        preferably, phenyl optionally substituted by cyano, carboxy,        protected carboxy or carbamoyl), saturated or unsaturated 5- or        6-membered heteromonocyclic group containing 1 to 2 nitrogen        atom(s) (more preferably, pyridinyl, pyrazinyl or piperazinyl)        optionally substituted by lower alkyl, or —CONR¹³R¹⁴ [wherein        R¹³ and R¹⁴ each independently represents hydrogen or lower        alkyl optionally substituted by aryl, or R¹³ and R¹⁴, together        with the nitrogen atom to which they are attached, represents        saturated 5- or 6-membered heteromonocyclic group containing 1        to 2 nitrogen atom(s) and also optionally containing oxygen        atom.] (more preferably, carbamoyl, methylcarbamoyl,        benzylcarbamoyl or morpholinylcarbonyl),    -   (8) aryl (more preferably, phenyl) optionally substituted by the        substituent(s) selected from the group consisting of halogen, or    -   (9) saturated or unsaturated 5- or 6-membered heteromonocyclic        group (more preferably, pyrrolidinyl, pyrrolyl, oxazolyl,        isooxazolyl, thiazolyl, furanyl, thienyl, pyridinyl) optionally        substituted by lower alkyl or halogen,-   R² is R⁷ or -(A¹)p-X-A²-R⁷    -   wherein    -   p is 0. or 1,    -   A¹ is (C₁-C₂)alkylene or —CH═CH—;    -   A² is —(CH₂)n- or —CH═CH)m- [wherein n is integer which may        range from 1 to 6 and m is integer which may range from 1 to 3];    -   X is single bond, —O—, —NR⁸—, —C(═O)—, —C(═NR⁹)— or        hydroxy(C₁-C₂)alkylene;    -   [wherein R⁸ is hydrogen or lower alkyl, and R⁹ is substituted or        unsubstituted pyrrolyl such as        2-ethyl-5-(4-fluorobenzoyl)pyrrolyl]    -   R⁷ is    -   (1) hydrogen,    -   (2) aryl (more preferably, phenyl) optionally substituted by        lower alkoxy,    -   (3) unsaturated heteromonocyclic group containing 1 to 2        nitrogen atom(s), (more preferably, pyridinyl),    -   (4) carboxy, esterified carboxy (more preferably, lower        alkoxycarbonyl) or —CONR¹⁰R¹¹ [wherein R¹⁰ and R¹¹ each        independently represents hydrogen, lower alkylsulfonyl,        unsaturated heteromonocyclic group containing 1 to 2 nitrogen        atom(s) such as pyridinyl or lower alkyl optionally substituted        by hydroxy, alkoxy, carboxy, protected carboxy, sulfo or —R¹⁷,        or alternatively R¹⁰ and R¹¹, together with the nitrogen atom to        which they are attached, represents saturated 5- or 6-membered        heteromonocyclic group containing 1 to 2 nitrogen atom(s) and        also optionally containing oxygen atom such as morpholinyl.],    -   (5) acyl (e.g. lower alkanoyl such as formyl or acetyl, and        heterocycliccarbonyl such as pyridinylcarbonyl) or halocarbonyl,    -   (6) cyano,    -   (7) amino, protected amino such as lower alkoxycarbonylamino, or        mono- or di(lower)alkylamino,    -   (8) hydroxy, aryloxy, acyloxy or lower alkoxy optionally        substituted by hydroxy or acyloxy (e.g. lower alkanoyloxy),    -   (9) lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl,        or    -   (10) —O—R¹²,    -   or-   R¹ and R² are combined together to form lower alkylene or lower    alkenylen group which is optionally interrupted by amino or sulfonyl    and also is optionally substituted by the group consisting of lower    alkyl, hydroxy, oxo and lower alkoxy, which is represented by the    following formula:    -   that may include the following ones;-   R³ is (1) aryl (more preferably, phenyl or naphthyl) optionally    substituted by at least one substituent(s) selected from the group    consisting of (i) halogen, (ii) carboxy, (iii) protected    carboxy, (iv) cyano, (v) —CONR¹⁵R¹⁶ [wherein R¹⁵ and R¹⁶ each    independently represents hydrogen, lower alkyl optionally    substituted by hydroxy], (vi) lower alkyl, (vii)    cyclo(lower)alkyl, (viii) hydroxy(lower)alkyl, (ix) lower    alkoxy, (x) trihalo(lower)alkyl, (xi) unsaturated 5- or 6-membered    heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 2    nitrogen atom(s) such as oxazolyl, (xii) lower alkylsulfonyl, (xiii)    nitro, (xiv) sulfamoyl, and (xv) protected sulfamoyl; or    -   (2) heterocyclic group selected from the group consisting of        pyridinyl, pyrazinyl, oxazolyl, isooxazolyl, furanyl, thienyl,        quinolyl, benzofuranyl and benzothienyl, wherein said        heterocyclic group is optionally substituted by at least one        substituent(s) selected from the group consisting of (i) lower        alkyl, (ii) cyclo(lower)alkyl, (iii) lower alkoxy, (iv) acyl        such as lower alkanoyl, (v) amino, (vi) mono- or        di(lower)alkylamino, (vii) protected amino such as lower        alkoxycarbonylamino, (viii) cyano, (ix) carboxy, (x) protected        carboxy such as ethoxycarbonyl or methoxycarbonyl, (xi)        —CONR¹⁵R¹⁶ [wherein R¹⁵ and R¹⁶ each independently represents        hydrogen, lower alkyl optionally substituted by hydroxy], (xii)        lower alkenyl optionally substituted by lower alkoxy, (xiii)        halogen, (xiv) lower alkylthio and (xv) hydroxy;-   R⁴ is hydrogen, halogen, cyano, carbamoyl, lower alkanoyl,    thiocyanate, lower alkylthio, lower alkenyl, hydroxyl(lower)alkyl,    trihalo(lower)alkyl or lower alkyl, and-   R¹² and R¹⁷ are each independently a group derived from protected or    unprotected sugar such as galactose by removal of the hydroxy group    therefrom,    or a pharmaceutically acceptable salt thereof.

More preferred compounds of formula (I) are those in which:

-   R¹ is (1) mono- or di(lower)alkylamino,    -   (2) aryl such as phenyl,    -   (3) satulated or unsaturated 5 to 6 membered heteromonocyclic        group containing 1 to 2 hetero atom(s) selected from nitrogen,        oxygen or sulfur atom(s) (more preferably, pyrrolidinyl,        pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, furanyl, thienyl,        pyridinyl, etc), or    -   (4) lower alkyl optionally substituted by lower alkoxy or        saturated 5- or 6-membered heteromonocyclic group containing 1        to 2 nitrogen atom(s) and also optionally containing oxygen atom        (more preferably, piperazinyl or morpholinyl), wherein lower        alkoxy is optionally substituted by cyclo(lower)alkyl or        unsaturated 5 to 6 membered heteromonocyclic group containing 1        to 2 nitrogen atom(s) (more preferably, pyridinyl),-   R² is R⁷ or -A²-R⁷, wherein    -   A² is —(CH₂)n- or —(CH═CH)m- [wherein n is integer which may        range 2 to 6 and    -   m is integer of 1 or 2, and    -   R⁷ is hydrogen, lower alkylsulfonyl, carboxy, protected carboxy        or unsaturated 5 to 6 membered heteromonocyclic group containing        1 to 2 nitrogen atom(s) (more preferably, pyridinyl),-   R³ is (1) aryl optionally substituted by lower alkyl,    cyclo(lower)alkyl, halogen, cyano or carbamoyl; or    -   (2) unsaturated condensed heterocyclic group containing 1 to 2        nitrogen atom(s) (more preferably, quinolinyl); or unsaturated 5        to 6 membered heteromonocyclic group containing at least one        nitrogen atom(s) (more preferably, 3-pyridinyl and 4-pyridinyl)        substituted by lower alkyl, cyclo(lower)alkyl or halogen, and-   R⁴ is lower alkyl.

Most preferred compounds of formula (I) are those in which:

-   R¹ is phenyl, satulated or unsaturated 5 to 6 membered    heteromonocyclic group containing 1 to 2 hetero atom(s) selected    from nitrogen, oxygen or sulfur atom(s) (more preferably, pyrrolyl,    isooxazolyl, furanyl, thienyl, etc.) or lower alkyl optionally    substituted by lower alkoxy or saturated or saturated 5- or    6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s)    and also optionally containing oxygen atom (more preferably,    piperazinyl or morpholinyl), wherein lower alkoxy is optionally    substituted by cyclo(lower)alkyl or unsaturated 5 to 6 membered    heteromonocyclic group containing at least one nitrogen atom(s)    (more preferably, pyridinyl),-   R² is —(CH₂)n-R⁷, wherein n is integer which may range 2 to 5, and    R⁷ is carboxy or protected carboxy,-   R³ is (1) phenyl optionally substituted by lower alkyl,    cyclo(lower)alkyl, lower alkoxy, halogen, cyano or carbamoyl; or (2)    unsaturated 5 to 6 membered heteromonocyclic group containing at    least one nitrogen atom(s) (more preferably, 3-pyridinyl and    4-pyridinyl) substituted by lower alkyl, cyclo(lower)alkyl, lower    alkoxy, carbamoyl or halogen, and-   R⁴ is lower alkyl.

Preferred concrete compound of formula (I) is:

-   (1)    3-[7-Ethyl-2-methyl-3-(4-pyridinyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,-   (2) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,-   (3)    4-[7-Ethyl-2-methyl-3-(methylsulfonyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,-   (4) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide,-   (5) Ethyl    5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate,-   (6)    2-{[4-(3-Chlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methyl}-1,3-propanediol,-   (7)    3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propanoic    acid,-   (8)    5-[7-Ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid,-   (9)    5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid,-   (10)    5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid,-   (11)    5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid,-   (12)    3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic    acid,-   (13)    5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid,-   (14) Ethyl    (2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenoate,-   (15)    6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic    acid-   (16)    3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic    acid,-   (17)    4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic    acid,-   (18)    5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid,-   (19)    5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic    acid.-   (20)    4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoic    acid,-   (21)    4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic    acid,-   (22)    4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic    acid,-   (23)    5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid, or-   (24)    5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic    acid,    or a pharmaceutically acceptable salt thereof.

More preferred concrete compound of formula (I) is:

-   (1) Ethyl    5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate,-   (2)    3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propanoic    acid,-   (3)    5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid,-   (4)    5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid,-   (5)    5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid,-   (6)    3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic    acid,-   (7)    5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid,-   (8)    6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic    acid-   (9)    3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic    acid,-   (10)    4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic    acid,-   (11)    5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid, and-   (12)    5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoic    acid,-   (13)    4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic    acid, or-   (14)    5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoic    acid,    or a pharmaceutically acceptable salt thereof.

The object compound (I) of the present invention can be prepared by thefollowing processes.

wherein R¹, R², R³ and R⁴ are each as defined above,

-   -   R¹ _(a) is the same as above R¹ having protected carboxy moiety,    -   R¹ _(b) is the same as above R¹ having carboxy moiety,    -   R¹ _(c) is —CONR⁵R⁶,    -   R¹ _(d) is carbamoyl(lower)alkyl,    -   R¹ _(e) is amino, mono- or di(lower)alkylamino-, lower        alkoxy(lower)alkylamino, nitrogen-containing heterocyclic group,        amino(lower)alkyl, mono- or di(lower)alkylamino(lower)alkyl,        lower alkoxy(lower)alkylamino(lower)alkyl, nitrogen-containing        heterocyclic(lower)alkyl,    -   R¹ _(f) is lower alkylthio(lower)alkyl,    -   R¹ _(g) is lower alkylsulfonyl(lower)alkyl,    -   R¹ _(h) is trifluoromethanesulfonyloxy or        trifluoromethanesulfonyloxy(lower)alkyl,    -   R¹ _(i) is lower alkoxy or lower alkoxy(lower)alkyl,    -   R¹ _(j) is hydroxy or hydroxy(lower)alkyl,    -   R¹ _(a) is lower alkoxycarbonyl,    -   R² _(b) is the same as above R² having protected carboxy moiety,    -   R² _(c) is the same as above R² having carboxy moiety,    -   R² _(d) is the same as above R² having carbamoyl moiety,    -   R² _(e) is the same as above R² having protected hydroxy moiety,    -   R² _(f) is the same as above R² having hydroxy moiety,    -   R² _(g) is the same as above R² having hydroxymethyl moiety,    -   R² _(h) is —OR¹²,    -   R² _(i) is lower alkoxycarbonyl or lower alkylsulfonyl,    -   R² _(j) is substituted or unsubstituted lower alkenyl as        mentioned in the above R², wherein said lower alkenyl is lower        1-alken-1-yl,    -   R² _(k) is the same as above R² having hydroxy(lower)alkyl        moiety,    -   R² _(l) is the same as above R² having oxo(lower)alkyl moiety,    -   R² _(m) is the same as above R² having protected amino moiety,    -   R² _(n) is the same as above R² having amino moiety,    -   R² _(m) is the same as above R² having protected hydroxy moiety,    -   R² _(p) is the same as above R² having        hydroxy(lower)alkylamino(lower)alkyl moiety,    -   R² _(q) is the same as above R² having lower        alkoxycarbonyl(lower)alkyl moiety,    -   R² _(f) is the same as above R² having lower        alkoxycarbonylmethylcarbonyl moiety,    -   R³ _(a) is the same as above R³ having cyano moiety,    -   R³ _(b) is the same as above R³ having carbamoyl moiety,    -   R³ _(c) is the same as above R³ having carboxy moiety,    -   R³ _(d) is the same as above R³ having protected sulfamoyl        moiety,    -   R³ _(e) is the same as above R³ having sulfamoyl moiety,    -   R³ _(f) is the same as above R³ having —CONR¹⁰R¹¹ moiety,    -   R³ _(g) is the same as above R³ having haloheterocyclic moiety,    -   R³ _(h) is the same as above R³ having alkoxyheterocyclic,        thioalkoxyheterocyclic or hydroxy moiety,    -   R³ _(i) is the same as above R³ having        1-(lower)alkoxy(lower)alken-1-ylheterocyclic moiety,    -   R³ _(j) is the same as above R³ having lower        alkanoylheterocyclic moiety,    -   R³ _(k) is the same as above R³ having aminomethylheterocyclic        moiety,    -   R³ _(l) is the same as above R³ having mono- or        di(lower)alkylaminoheterocyclic moiety,    -   R³ _(m) is the same as above R³ having        (lower)alken-1-ylheterocyclic group or        1-(lower)alkoxy-1-(lower)alken-1-yl-heterocyclic moiety,    -   R⁴ _(a) is halogen,    -   R⁴ _(b) is formyl,    -   R⁴ _(c) is lower 1-alken-1-yl,    -   R⁴ _(d) is lower alkyl,    -   R¹² is lower alkyl or a group derived from protected or        unprotected sugar by removal of the hydroxy group therefrom,    -   X is a leaving group, and    -   a group of the formula:        is lower alkylene interrupted by imino moiety and substituted by        oxo groups.

The starting compound (II) of the present invention can be preparedaccording to a conventional manner or in a similar manner as describedin the following Preparations and/or Examples.

Another point to be noted is that the pyrrolopyridazine moiety of thecompound (I) can also exist in the tautomeric form, and such tautomericequilibrium can be represented, for example, by the following formula.

wherein R¹ R², R³ and R⁴ are each as defined above.

Both of the above tautomeric isomers are included within the scope ofthe present invention, and in the present specification and claims,however, the object compound (I) is represented for convenience’ sake byone expression of the possible tautomeric forms of pyrrolopyridazinering.

In the above and subsequent descriptions of the present specification,suitable examples and illustration of the various definitions which thepresent invention intends to include within the scope thereof areexplained in detail as follows.

The term “lower” is used to intend a group having 1 to 6, preferably 1to 4, carbon atom(s), unless otherwise provided.

Suitable “lower alkyl” and “lower alkyl moiety” may include straight orbranched one having 1 to 6 carbon atom(s), such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,tert-pentyl, hexyl, and the like, and in which more preferable examplemay be C₁-C₄ alkyl.

Suitable “lower alkenyl” may include vinyl(ethenyl), 1-(or 2-)propenyl,1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 4-)pentenyl, 1-(or 2- or 3- or4- or 5-)hexenyl, 1-methylvinyl, 1-ethylvinyl, 1-(or 2-)methyl-1-(or2-)propenyl, 1-(or 2-)ethyl-1-(or 2-)propenyl, 1-(or 2- or3-)methyl-1-(or 2- or 3-)butenyl, and the like, in which more preferableexample may be C₂-C₄ alkenyl.

Suitable “lower alkynyl” may include ethynyl, 1-propynyl, propargyl,1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or2 or 3 or 4 or 5-hexynyl, and the like.

Suitable “lower alkylene” may include straight or branched one such asmethylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene, methylmethylene, ethylethylene, propylene, and the like,in which more preferable example may be C₁-C₄ alkylene and the mostpreferable one may be methylene.

Example of hydroxy(C₁-C₂)alkylene is hydroxymethylene,(hydroxymethyl)methylene or 1-(or 2-)hydroxyethylene.

Suitable “lower alkoxy” may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy,hexyloxy and the like.

Suitable “halogen” and “halogen moiety” may include fluorine, bromine,chlorine and iodine.

Suitable “trihalo(lower)alkyl” may include trichloromethyl,trifluoromethyl, trichloroethyl, tribromoethyl, and the like.

Suitable “mono- or di(lower)alkylamino” may include amino groupsubstituted by one or two lower alkyl such as methylamino, ethylamino,dimethylamino, and the like.

Example of “mono- or di(lower)alkylamino substituted by lower alkoxy”may be methoxymetylamino, methoxyethylamino, methoxyethyl(methyl)amino,methoxyethyl(ethyl)amino, di(methoxyethyl)amino, ethoxymethylamino,ethoxyethylamino, and the like.

Suitable “lower alkylthio” may include conventional ones such asmethylthio, ethylthio, propylthio, butylthio, and the like.

Suitable “lower alkylsulfinyl” may include conventional ones such asmethylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and thelike.

Suitable “lower alkylsulfonyl” may include conventional ones such asmethylsulfonyl, ethylsulfonyl, propylsulfonyl, bytylsulfonyl, and thelike.

Suitable “trihalo(lower)alkylsulfonyloxy” may include sulfonyloxy groupsubstituted by trihalo(lower)alkyl such as trifluoromethylsulfonyloxy,trifluoroethylsulfonyloxy, trichloromethylsulfonyloxy, and the like.

Suitable “protected carboxy” and “protected carboxy moiety” may includeesterified carboxy and the like.

And suitable example of said ester may be the ones such as

-   lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester,    isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl    ester, t-pentyl ester, hexyl ester, etc.);-   lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.);-   lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.);-   lower alkoxy(lower)alkyl ester (e.g., methoxymethyl ester,    ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester,    1-ethoxyethyl ester, etc.);-   lower alkylthio(lower)alkyl ester (e.g., methylthiomethyl ester,    ethylthiomethyl ester, ethylthioethyl ester, isopropoxythiomethyl    ester, etc.);-   mono(or di or tri)halo(lower)alkyl ester (e.g., 2-iodoethyl ester,    2,2,2-trichloroethyl ester, etc.);-   lower alkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester,    propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl    ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester,    1-acetoxyethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl    ester, etc.);-   lower alkoxycarbonyloxy(lower)alkyl ester (e.g.,    methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester,    propoxycarbonyloxymethyl ester, 1-(or 2-)-[methoxycarbonyloxy]ethyl    ester, 1-(or 2-)-[ethoxycarbonyloxy]ethyl ester, 1-(or    2-)-[propoxycarbonyloxy]ethyl ester, 1-(or    2-)-[isopropoxycarbonyloxy]ethyl ester, etc.);-   lower alkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester,    2-mesylethyl ester, etc.);-   lower alkoxycarbonyloxy(lower)alkyl ester (e.g.,    methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester,    propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester,    1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or    2-)-ethoxycarbonyloxyethyl ester, 1-(or    2-)-isopropoxycarbonyloxyethyl ester, etc.);-   phthalidylidene(lower)alkyl ester;-   (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g.,    (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,    (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,    (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.];-   mono(or di or tri)aryl(lower)alkyl ester, for example, mono(or di or    tri)phenyl(lower)alkyl ester which may have one or more suitable    substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester,    4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl    ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester,    4-hydroxy-3,5-di-t-butylbenzyl ester, etc.);-   aryl ester which may have one or more suitable substituent(s) such    as substituted or unsubstituted phenyl ester (e.g., phenyl ester,    tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester,    cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.);-   tri(lower)alkylsilyl ester (e.g. trimethylsilyl ester, triethylsilyl    ester, etc.); tri(lower)alkylsilyl(lower)alkyl ester (e.g.    2-trimethylsilylethyl ester, etc.);    and the like, in which more preferable example may be lower alkyl    ester, i.e., lower alkoxycarbonyl (e.g. ethoxycarbonyl, etc.).

The term “protected amino” means an amino group bonded to theamino-protecting group. Example of such amino-protectnig group includelower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl, etc.); lower alkenyloxycarbonyl (e.g.vinyloxycarbonyl, allyloxycarbonyl, etc.); optionally substitutedaryl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.); phthalimide;and the like. Further example of amino-protecting group are well-knownin organic synthesis and are described by T. W. Greene and P. G. M.Wuts, “Protective Groups in Organic Synthesis,” Second Edition, JohnWiley and Sons, New York, N.Y., which is herein incorporated byreference.

The term “protected sulfamoyl” means sulfamoyl group having theamino-protecting group mentioned above on the nitrogen atom. A preferredamino-protecting group is aryl(lower)alkoxycarbonyl (e.g.benzyloxycarbonyl, etc.); and the like.

Suitable “acyl” and “acyl moiety” may include aliphatic acyl group, andacyl group containing an aromatic ring, which is referred to as aromaticacyl, or heterocyclic ring, which is referred to as heterocyclic acyl.

Suitable example of said acyl may be illustrated as follows:

-   Aliphatic acyl such as-   lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl,    2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl,    heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl,    tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl,    heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); in    which preferable “lower alkanoyl” may include straight or branched    one such as formyl, acetyl, propionyl, butyryl, and the like.-   lower or higher alkenoyl (e.g., acryloyl, 2-(or 3-)-butenoyl, 2-(or    3- or 4-)pentenoyl, 2-(or 3- or 4- or 5-)-hexenoyl, etc.);-   lower alkadienoyl (e.g., heptadienoyl, hexadienoyl, etc.);-   cyclo(lower)alkylcarbonyl (e.g., cyclopropylcarbonyl,    cyclopentylcarbonyl, cyclohexylcarbonyl, etc.);-   lower alkylglyoxyloyl (e.g., methylglyoxyloyl, ethylglyoxyloyl,    propylglyoxyloyl, etc.);-   lower alkoxyglyoxyloyl (e.g., methoxyglyoxyloyl, ethoxyglyoxyloyl,    propoxyglyoxyloyl, etc.);    or the like;-   Aromatic acyl such as-   aroyl (e.g., benzoyl, toluoyl, naphihoyl, etc.);-   ar(lower)alkanoyl [e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl,    phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl,    phenylhexanoyl, etc.), naphthyl(lower)alkanoyl (e.g.,    naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];-   ar(lower)alkenoyl [e.g., phenyl(lower)alkenoyl (e.g.,    phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl,    phenylpentenoyl, phenylhexenoyl, etc.), naphthyl(lower)alkenoyl    (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.];-   aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl,    etc.);-   arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.);-   heterocyclic acyl such as heterocycliccarbonyl;-   heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl,    heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl,    heterocyclichexanoyl, etc.);-   heterocyclic(lower)alkenoyl(e.g., heterocyclicpropenoyl,    heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl,    etc.);-   heterocyclicglyoxyloyl; heterocyclicoxycarbonyl; or the like;    in which suitable “heterocyclic moiety” may include saturated or    unsaturated, monocyclic or polycyclic heterocyclic group containing    at least one hetero-atom such as an oxygen, sulfur, nitrogen atom    and the like, as mentioned below and preferable    “heterocyclic-carbonyl” may include carbonyl group substituted by    heterocyclic group as mentioned below such as pyrrolidinylcarbonyl,    pyridinylcarbonyl, pyrazinylcarbonyl, and the like.

Syitable “halocarbonyl” may include chlorocarbonyl, bromocarbonyl, andthe like.

Suitable “cyclo(lower)alkyl” and “cyclo(lower)alkyl moeity” may includeone having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

Suitable “aryl” and “aryl moiety” may include C₆-C₁₀ aryl such asphenyl, naphthyl and the like.

Suitable “heterocyclic moiety” may include saturated or unsaturated,monocyclic or polycyclic heterocyclic group containing at least onehetero-atom such as an oxygen, sulfur, nitrogen atom and the like.

Preferable heterocyclic group may be heterocyclic group such as

-   (1) unsaturated 3 to 8-membered (more preferably 5 or 6-membered)    heteromonocyclic group containing 1 to 4 nitrogen atom(s), for    example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl,    dihydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl    (e.g., 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,    2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl,    2H-tetrazolyl, etc.), etc.;-   (2) saturated 3 to 8-membered (more preferably 5 or 6-membered)    heteromonocyclic group containing 1 to 4 nitrogen atom(s), for    example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;-   (3) unsaturated condensed heterocyclic group containing 1 to 4    nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl,    indolizinyl, benzimidazolyl, quinolyl, tetrahydroquinolyl (e.g.,    1,2,3,4-tetrahydroquinolyl, etc.), isoquinolyl, indazolyl,    benzotriazolyl, benzopyrimidinyl (e.g., benzo[b]pyrimidinyl, etc.),    etc.;-   (4) unsaturated 3 to 8-membered (more preferably 5 or 6-membered)    heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3    nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl    (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl,    etc.), etc.;-   (5) saturated 3 to 8-membered (more preferably 5 or 6-membered)    heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3    nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;-   (6) unsaturated condensed heterocyclic group containing 1 to 2    oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,    benzoxazolyl, benzoxadiazolyl, etc.;-   (7) unsaturated 3 to 8-membered (more preferably 5 or 6-membered)    heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3    nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl    (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,    1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;-   (8) saturated 3 to 8-membered (more preferably 5 or 6-membered)    heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3    nitrogen atom(s), for example, thiazolidinyl, etc.;-   (9) unsaturated 3 to 8-membered (more preferably 5 or 6-membered)    heteromonocyclic group containing 1 to 2 sulfur atom(s), for    example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;-   (10) unsaturated condensed heterocyclic group containing 1 to 2    sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,    benzothiazolyl, benzothiadiazolyl, etc.;-   (11) unsaturated 3 to 8-membered (more preferably 5 or 6-membered)    heteromonocyclic group containing an oxygen atom, for example,    furanyl, etc.;-   (12) unsaturated condensed heterocyclic group containing 1 to 2    oxygen atom(s), for example, benzodioxolyl (e.g.    methylenedioxyphenyl, etc.), benzofuranyl, etc.;-   (13) unsaturated 3 to 8-membered (more preferably 5 or 6-membered)    heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur    atom(s), for example, dihydrooxathiinyl, etc.;-   (14) unsaturated condensed heterocyclic group containing 1 to 2    sulfur atom(s), for example, benzothienyl (e.g., benzo[b]thienyl,    etc.), benzodithiinyl, etc.;-   (15) unsaturated condensed heterocyclic group containing an oxygen    atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc.;    and the like.

Suitable “heterocyclic group” and “heterocyclic moiety” in the terms“heterocycliccarbonyl” can be referred to the ones as mentioned above.

Suitable “N-containing heterocyclic group” and “N-containingheterocyclic moiety” can be referred to the ones as mentioned above,wherein the heterocyclic group is containing at least one nitrogen atomsuch as 1-pyrrolidinyl, morpholinyl and the like.

A group derived from a sugar may be the group derived from, for example,glyceraldehydes; an aldose such as erythrose, threose, arabinose,ribose, xylose, lyxose, glucose, mannose or galactose; a ketose such asfructose or sorbose; or a discccharide such as maltose, lactose orsucrose.

Protecting groups for the hydroxy group of the above-mentioned sugarsare an aliphatic acyl group, such as formyl, or acetyl; a cyclic ethergroup such as tetrahydro-2-furanyl or tetrahydro-2-pyranyl; a1-alkoxyethyl group such as 1-methoxyethyl or 1-ethoxyethyl; and a silylgroup such as trimethylsilyl, triethylsilyl or t-butyldimethylsilyl.

Suitable “substituted or unsubstituted lower alkyl” for R¹ may includestraight or branched lower alkyl (e.g. methyl, isopropyl, neopentyl,etc.) optionally substituted by; (1) halogen (e.g. fluoro, bromo, etc.),(2) carboxy, (3) protected carboxy (e.g. esterified carboxy such asethoxycarbonyl, etc.), (4) cyano, (5) carbamoyl, (6) —OCONR¹⁵R¹⁶[wherein R¹⁵ and R¹⁶ each independently represents hydrogen, aryl orlower alkyl optionally substituted by aryl, or R¹³ and R¹⁴, togetherwith the nitrogen atom to which they are attached, represents saturated5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogenatom(s) and also optionally containing oxygen atom.] (more preferably,dimethylcarbamoyloxy, methyl-phenylcarbamoyloxy, morpholinylcarbonyloxy,pyrrolidinylcarnbonyloxy, etc); (7) lower alkylthio (e.g. methylthio,etc.), (8) lower alkylsulfonyl (e.g. methylsulfonyl, etc.), (9) loweralkylsulfonyloxy (e.g. methylsulfonyoxyl, etc.), (10) loweralkylsulfonylamino (e.g. methylsulfonylamino, etc.), (11) mono- ordi(lower)alkylamino optionally substituted by hydroxy, lower alkoxy,acyloxy (e.g. phenoxy, etc.), or substituted or unsubstituted aryl (e.g.benzylamino, etc.), (12) amino; (13) acylamino (more preferably, loweralkanoylamino such as acetylamino, aroylamino such as benzoylamino, orheterocycliccarbonylamino such as pyrazinylcarbonylamino, or the like),(14) protected amino (e.g., methoxycarbonylamino, phthalimide, etc.),(15) hydroxy, (16) acyloxy (more preferably, lower alkanoyloxy such asacetyloxy, or the like), (17) cyclo(lower)alkyloxy, (18) aryloxy (e.g.phenoxy, etc.) (19) substituted or unsubstituted aryl (more preferably,phenyl), (20) saturated or unsaturated 5- or 6-membered heteromonocyclicgroup containing 1 to 3 nitrogen atom(s) and also optionally containingoxygen atom or sulfur atom (more preferably, piperazinyl, morpholinyl,oxazolidinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or triazolyl)optionally substituted by lower alkyl, hydroxy(lower)alkyl, aryl or oxo,(21) lower alkoxy (e.g. methoxy, ethoxy, iso-propoxy, etc.) optionallysubstituted by carboxy, protected carboxy (e.g. tert-butoxycarbonyl,etc.), hydroxy, protected hydroxy (e.g. tetrahydro-2H-pyran-2-yloxy,etc.), cyclo(lower)alkyl (e.g. cyclopropyl, cyclohexyl, etc.),substituted or unsubstituted aryl (e.g. phenyl optionally substituted bycyano, carboxy, protected carboxy or carbamoyl, such as phenyl, 2-, 3-or 4-cyanophenyl, 2-, 3- or 4-carboxyphenyl, 2-, 3- or4-(methoxycarbonyl)phenyl, 2-, 3- or 4-carbamoylphenyl, etc.), saturatedor unsaturated 5- or 6-membered heterocyclic group containing 1 to 2nitrogen atom(s) optionally substituted by lower (more preferably, 2-,3- or 4-pyridinyl, pyrazinyl or 4-methylpiperazinyl)(e.g. 2-, 3- or4-pyridinyl, pyrazinyl, etc.), or —CONR¹³R¹⁴ [wherein R¹³ and R¹⁴ eachindependently hydrogen or lower alkyl optionally substituted by aryl, orR¹³ and R¹⁴, together with the nitrogen atom to which they are attached,represents N-containing heterocyclic group] (e.g. morpholinocarbonyl,dimethylcarbamoyl, etc.), and the like.

Suitable “substituted or unsubstituted aryl” may include C₆-C₁₀ aryl(e.g. phenyl, naphthyl, etc.) optionally substituted by thesubstituent(s) selected from the group consisting of (1) halogen (e.g.fluoro, chloro, etc.), (2) carboxy, (3) protected carboxy, (4) cyano,(5) —CONR¹⁵R¹⁶ [wherein R¹⁵ and R¹⁶ are each independently representshydrogen, lower alkyl optionally substituted by hydroxy] (e.g.carbamoyl, hydroxyethylcarbamoyl, etc.), (6) lower alkyl (e.g. methyl,etc.), (7) cyclo(lower)alkyl (e.g. cyclopropyl, etc) (8) lower alkoxy(e.g. methoxy, etc.), (9) trihalo(lower)alkyl (e.g. trifluoromethyl,etc.), (10) heterocyclic group such as oxazolyl, (11) loweralkylsulfonyl (e.g. methylsulfonyl, etc.), (12) nitro, (13) amino, (14)sulfamoyl, and (15) protected sulfamoyl such asar(lower)alkoxycarbonylsulfamoyl, and the like.

In which,

preferable example of “substituted or unsubstituted aryl” for R¹ is aryloptionally substituted by the substituent(s) selected from the groupconsisting of halogen (e.g. phenyl, 4-fluorophenyl, etc.);

preferable example of “substituted or unsubstituted aryl” for R³ is aryloptionally substituted by the substituent(s) selected from the groupconsisting of (1) halogen, (2) carboxy, (3) protected carboxy such asesterified carboxy (e.g. benzyloxycarbonyl, etc,), (4) cyano, (5)—CONR¹⁵R¹⁶ [wherein R¹⁵ and R¹⁶ are each independently representshydrogen, lower alkyl optionally substituted by hydroxy], (6) loweralkyl, (7) cyclo(lower)alkyl, (8) lower alkoxy, (9) trihalo(lower)alkyl,(10) heterocyclic group, (11) lower alkylsulfonyl, (12) nitro, (13)amino, (14) sulfamoyl, and (15) protected sulfamoyl, and the like. (e.g.phenyl, 2-naphthyl, 2- or 3-chlorophenyl, 2,3-, 2,4-, 3,4- or3,5-dichlorophenyl, 3- or 4-fluorophenyl, 3- or 4-cyanophenyl, 3- or4-carbamoylphenyl, 4-sulfamoylphenyl,4-(benzyloxycarbonylsulfamoyl)phenyl, 3-carboxyphenyl,3-(N-(2-hydroxyethyl)carbamoyl)phenyl, 3-nitrophenyl,3-trifluoromethylphenyl, 3-methylsulfonylphenyl, 3-(5-oxazolyl)phenyl,3-methoxyphenyl, 3-methylphenyl, etc.); and

preferable example of “substituted or unsubstituted aryl” for R⁷ is aryloptionally substituted by lower alkoxy (e.g. phenyl, 2-, 3- or4-methoxyphenyl, etc.).

Suitable “substituted or unsubstituted heterocyclic group” may includeheterocyclic group mentioned above (more preferably, pyridinyl,pyrazinyl, oxazolyl, isooxazolyl, furanyl, thienyl, quinolinyl,benzofuranyl and benzothienyl), which is optionally substituted by thesubstituent(s) selected from the group consisting of (1) lower alkyl(e.g. methyl, etc.), (2) cyclo(lower)alkyl (e.g. cyclopropyl, etc.) (3)lower alkoxy (e.g. methoxy, etc.), (4) acyl (e.g. lower alkanoyl such asacetyl, etc.), (5) amino, (6) mono- or di(lower)alkylamino (e.g.dimethylamino, etc.), (7) protected amino (e.g. loweralkoxycarbonylamino such as tert-butoxycarbonylamino, etc.), (8) cyano,(9) carboxy, (10) protected carboxy (e.g. benzyloxycarbonyl, etc.), (11)—CONR¹⁵R¹⁶ [wherein R¹⁵ and R¹⁶ are each independently representshydrogen, lower alkyl optionally substituted by hydroxy] (e.g.carbamoyl, hydroxyethylcarbamoyl, etc.), (12) lower alkenyl optionallysubstituted by lower alkoxy (e.g. vinyl, 1-ethoxyvinyl, etc.), (13)halogen (e.g. chloro, bromo, etc.), (14) lower alkylthio, (15) hydroxy,and the like.

In which,

preferable example of “substituted or unsubstituted heterocyclic group”for R¹ is heterocyclic group optionally substituted by lower alkyl orhalogen (e.g. 2-pyridinyl, 5-blomo-3-pyridinyl, 1-methyl-2-pyrrolyl,1-pyrrolyl, 1-pyrrolidinyl, 3-methyl-2-thienyl, 2-thienyl, 2- or3-furanyl, 2-thiazolyl, 5-oxazolyl, 5-methyl-isooxazolyl,3,5-dimethyl-4-isoxazolyl, etc.); and

preferable example of “substituted or unsubstituted heterocyclic group”for R³ is heterocyclic group optionally substituted by at least onesubstituent(s) selected from the group consisting of (1) lower alkyl,(2) cyclo(lower)alkyl, (3) lower alkoxy, (4) acyl such as loweralkanoyl, (5) amino, (6) mono- or di(lower)alkylamino, (7) protectedamino such as lower alkoxycarbonylamino, (8) cyano, (9) carboxy, (10)protected carboxy such as esterified carboxy (e.g. benzyloxycarbonyl),(11) carbamoyl, (12) lower alkenyl optionally substituted by loweralkoxy, (13) halogen, (14) lower alkylthio, and (15) hydroxy (e.g. 3- or4-pyridyl, 2-pyrazinyl, 6-methoxy-2-pyrazinyl, 4- or 5-oxazolyl,2-benzofuranyl, 2-benzothienyl, 3- or 6-quinolinyl, 2-chloro-4-pyridyl,5-bromo-3-pyridyl, 5-chloro-2-thienyl, 5,6-dichloro-2-pyridyl,4-chloro-2-pyridyl, 5-cyano-3-pyridyl, 5-carboxy-3-pyridinyl,5-carbamoyl-3-pyridyl, 5-(benzyloxycarbonyl)-3-pyridyl,5-(tert-butoxycarbonylamino)-3-pyridinyl, 5-amino-3-pyridinyl,2-methoxy-4-pyridyl, 3-methoxy-5-isoxazolyl, 2-methylthio-4-pyridinyl,2-hydroxy-4-pyridyl, 5-methyl-3-pyridyl, 5-ethyl-3-pyridyl,5-methyl-3-isoxazolyl, 5-vinyl-3-pyridyl, 2-vinyl-4-pyridyl,5-acetyl-3-pyridyl, 2-dimethylamino-4-pyridyl,5-(1-ethoxyvinyl)-3-pyridyl, 2-oxo-1,2-dihydro-4-pyridyl, or2-methylthio-4-pyridyl, etc.).

R¹ and R² are combined together to form lower alkylene or loweralkenylen group which is optionally interrupted by amino or sulfonyl andalso is optionally substituted by the group consisting of lower alkyl,hydroxy, oxo and lower alkoxy, which is represented by the followingformula:

The above formula may include following ones;

Suitable “substituted or unsubstituted aryl(lower)alkenyl” may includeC₆-C₁₀ aryl(lower)alkenyl which is optionally substituted by halogen(e.g. 2-phenylvinyl, 2-(2- or 3-chlorophenyl)vinyl, etc.).

Suitable “leaving group” may include acid residue, lower alkoxy asexemplified above, and the like.

The above Processes can be carried out according to a conventionalmanner such as the one described in Preparations and/or Examples, or ina similar manner thereto. Among the above Processes, fused heterocyclicring forming processes (such as Process 1 and Process 12) are importantfor carrying out of this invention and are explained in more detail.

According to the Process 1, pyrrolopyridazine derivatives (I) can beprepared by reacting the 1-amino-2-acylpyrrole derivative (II) or a saltthereof and the compound (III) or a salt thereof in the presence of acatalytic amount of acid catalyst in an inert solvent, preferably withconcomitant removal of the water being produced by physical (e.g.Dean-Stark trap) or chemical (e.g. molecular sieves) means. Suitableacid catalyst is, for example p-toluenesulfonic acid, methanesulfonicacid, hydrochloric acid, trifluoroacetic acid and so on. Suitable inertsolvent is, for example, benzene, toluene, tetrahydrofuran and the like.

Another ring forming process is descried in Process 12, in this processpyrrolopyridazine derivatives (I) can be also prepared reacting1-aminopyrole derivative (V) or a salt thereof and β-diketone derivativeor a salt thereof under the similar condition before mentioned Process1, and therefore the reaction conditions can be referred to those of theProcess 1.

The compounds of the present invention can be purified by anyconventional purification methods employed for purifying organiccompounds, such as re-crystallization, column chromatography, thin-layerchromatography, high-performance liquid chromatography and the like. Thecompounds can be identified by conventional methods such as NMRspectrography, mass spectrography, IR spectrography, elemental analysis,and measurement of melting point.

Suitable salts of the object and the starting compounds in Processes 1to 40 can be referred to the ones as exemplified for the compound (I).

The new pyrrolopyridazine derivatives (I) and pharmaceuticallyacceptable salts thereof hardly possess a strong inhibitory activityagainst phosphodiesterase III (PDE III), but possess a strong inhibitoryactivity against phosphodiesterase IV (PDE IV) and a strong inhibitoryactivity on the tumor necrosis factor (TNF).

That is, the pyrrolopyridazine derivatives (I) and pharmaceuticallyacceptable salts thereof are selective inhibitors of phosphodiesteraseIV (PDE IV) and inhibitors on the production of tumor necrosis factor(TNF).

Accordingly, the new pyrrolopyridazine derivatives (I) and apharmaceutically acceptable salt thereof can be used for prophylacticand therapeutic treatment of PDE-IV and TNF mediated diseases such aschronic inflammatory diseases (e.g., rheumatoid arthritis,osteoarthritis, emphysema, chronic bronchiolitis, allergic rhinitis,etc.), osteoporosis, rejection by transplantation, asthma, chronicobstructive pulmonary disease (COPD), eosinophilia, fibrotic disease(e.g., cystic fibrosis, pulmonary fibrosis, hepatic fibrosis, renalfibrosis, etc.), (viral alcoholic, drug-induced) acute and fulminanthepatitis, hepatic steatosis (alcoholic and non-alcoholicsteato-hepatitis), chronic (viral and non-viral) hepatitis, hepaticcirrhosis, autoimmune hepatitis, pancreatitis, nephritis, endotoxinshock, specific autoimmune diseases [e.g., ankylosing spondylitis,autoimmune encephalomyelitis, autoimmune hematological disorders (e.g.,hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathicthrombocytopenia, etc.), systemic lupus erythematosus (SLE),polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis,chronic active hepatitis (Wilson's disease, etc.), myasthenia gravis,idiopathic sprue, autoimmune inflammatory bowel disease (e.g.,ulcerative colitis, Crohn's disease, etc.), endocrine ophthalmopathy,Grave's disease, sarcoidosis, multiple sclerosis, primary biliarycirrhosis, juvenile diabetes (diabetes mellitus type I), Reiter'ssyndrome, non infection uveitis, autoimmune keratitis (e.g.,keratoconjunctivitis sicca, vernal keratoconjunctivitis, etc.),interstitial lung fibrosis, psoriatic arthritis, etc.], dermatologicaldisorders associated with PDE-IV enzyme (such as psoriasis and otherbenign or malignant proliferative skin diseases, atopic dermatitis, andurticaria), neurodegenerative disorders such as Parkinson disease,Alzheimer's disease, acute and chronic multiple sclerosis, cancercachexia, viral infection, AIDS cachexia, thrombosis, and the like.

For therapeutic administration, the compound (I), or its prodrug, or asalt thereof can be administered alone or in the form of a mixture,preferably, with a pharmaceutical vehicle or carrier.

The active ingredient of this invention can be used in the form of apharmaceutical preparation, for example, in solid, semisolid or liquidform, which contains a compound (I), as an active ingredient, inadmixture with an organic or inorganic carrier or excipient suitable forexternal (topical), enteral, intravenous, intramuscular, parenteral orintra-mucous applications. The active ingredient can be formulated, forexample, with the conventional non-toxic, pharmaceutically acceptablecarriers for ointment, cream, plaster, tablets, pellets, capsules,suppositories, solution (saline, for example), emulsion, suspension(olive oil, for example), aerosols, pills, powders, syrups, injections,troches, cataplasms, aromatic waters, lotions, buccal tablets,sublingual tablets, nasal drops and any other form suitable for use. Thecarriers which can be used are water, wax, glucose, lactose, gum acacia,gelatin, mannitol, starch paster, magnesium trisilicate, talc, cornstarch, keratin, paraffin, colloidal silica, potato starch, urea andother carriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form, and in addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. The activecompound is included in a pharmaceutical composition in an effectiveamount sufficient to produce the desired effect upon the process orcondition of the diseases.

The active ingredient can be formulated into, for example, preparationsfor oral application, preparations for injection, preparations forexternal application, preparations for inhalation, and preparations forapplication to mucous membranes.

Further, the compound of this invention can be used in combination withother therapeutic compounds. In particular, the combinations of the PDE4inhibiting compound of this invention can be advantageously used incombination with i) Leukotriene receptor antagonists, ii) Leukotrienebiosynthesis inhibitors, iii) COX-2 selective inhibitors, iv) statins,v) NSAIDs, vi) M2/M3 antagonists, vii) corticosteroids, viii) Hi(histamine) receptor antagonists, ix) beta 2 adrenoceptor agonist, x)interferon, xi) antiviral drugs for hepatitis C virus (HCV) such asprotease inhibitor, helicase inhibitor, polymerase inhibitor, or thelike, xii) antiviral drug for hepatitis B virus such as lamivudine,xiii) ursodesoxycholic acid, xiv) glycyrrhizin, xv) human grouth factor(HGF), xvi) aminosalicylic acid such as salazosulfapyridine, mesalazin,or the like, xvii) steroids such as prednisolone farnesylate, xviii)immunosuppressant such as azathioprine, 6-mercaptopurine, tacrolimus,and the like.

Mammals which may be treated by the present invention include livestockmammals such as cows, horses, etc., domestic animals such as dogs, cats,rats, etc. and humans, preferably humans.

While the dosage of therapeutically effective amount of the compound (I)will vary depending upon the age and condition of each individualpatient, an average single dose to a human patient of about 0.01 mg, 0.1mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mg of thecompound (I) may be effective for treating the above-mentioned diseases.In general, amounts between 0.01 mg/body and about 1,000 mg/body may beadministered per day.

In order to show the utilities of the pyrrolopyridazine derivatives (I)and a pharmaceutically acceptable salt thereof of the present invention,pharmacological test data of the representative compound of thepyrrolopyridazine derivatives (I) are illustrated in the following.

(a) Inhibition of U937 Phosphodiesterase IV (PDE IV)

1. Test Method:

Cultured U937 cells were washed twice and harvested withphosphate-buffered saline (PBS) by cell-scraper. After centrifugation,the cell pellet was suspended in homogenizing buffer (0.5% deoxycholate[DOC], 5 mM 2-mercaptoethanol, 1 μM leupeptin, 100 μM PMSF, 20 μMp-tosyl-L-lysine-chloromethyl ketone [TLCK] in PBS). The cell suspensionwas then sonicated for a couple of minutes and homogenized by aglass-Teflon homogenizer with twenty strokes. The homogenate wascentrifuged at 200 g for 30 minutes, and the supernatant was furtherultra-centrifuged at 100,000×g for 90 minutes (4° C.). The finalsupernatant was dialyzed against dialysis buffer, which was the samecomponent as homogenizing buffer without DOC. The dialysate of enzymepreparation was stored at −20° C. until assay.

PDE4, activity was estimated with a Phosphodiesterase [³H]cAMP SPAEnzyme Assay System (Amersham Pharmacia Biotech), using a 96 wellOpti-plate. Reactions were initiated by addition of 0.025 μCi/well of[³H]cAMP to the enzyme mixture containing 50 mM Tris-HCl (pH 7.5), 8.3mM MgCl₂, 1.7 mM EGTA, and various concentrations of the test compoundor vehicle. CI-930 (10 μM in final), a specific PDE3, inhibitor, wasalso added in the reaction mixture. After incubation at 30° C. for 15minutes, 50 μL of SPA beads suspension was added to each well. Thewell-plate was then shaken for 20 minutes by a plate mixer.Radio-activity in each well was counted by a Top Counter.

Test compounds were dissolved in 100% dimethylsulfoxide (DMSO) anddiluted into respective concentrations with the final solutioncontaining 1% v/v of DMSO.

IC₅₀ values of test compounds for the enzyme activity of PDE4 wasdetermined from regression analysis for log-logit conversion values ofpercent inhibition in the compound-treated tubes compared to that of thecontrol. Percent inhibition was calculated with the following equation:Inhibition (%)={1−(C−B)/(A−B)}×100; in which A, B and C means meanvalues of radio-activity counts (dpm) of control, blank and thecompound-treated tubes, respectively.

2. Test Results

The following table illustrates the inhibitory activity on PDE-IV of therepresentative compound of formula (I): Example Compound name IC50 (μM)198 6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2- <1methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid(b) Inhibition on TNF-Alpha Production in Human Mononuclear Cells1. Test Method(1) Human Peripheral Blood Mononuclear Cells (PBMCs) Preparation

Blood (30 ml for each person) was collected from the median cubital veinof healthy volunteer was divided 15 mL each in heparin containingconical tube and the same volume of RPMI1640 was added to each tube.Diluted blood was then piled up to 20 mL of Ficoll-Paque PLUS (AmershamPharmacia Biotech) in polystyrene centrifuge tube. After centrifugationat 1,600 rpm for 30 minutes, cells gathering in the center area of thegradient were collected by capillary and washed with 40 mL of RPMI1640in several times with centrifugation at 1,200 rpm for 10 minutes. PBMCfinally precipitated were suspended in RPMI1640 containing 1% fetalbovine serum and antibiotics. After cell counting, final suspension at3×10⁶ cells/mL in culture medium was prepared.

(2) TNF-Alpha Production from Stimulated PBMCs

Human PBMCs prepared by the density gradient method using Ficoll-PaquePLUS were suspended in the culture medium mentioned above with theconcentration of 3×10⁶ cells/mL and 0.5 mL of the suspension was sowedinto each well of a 24-well culture plate. Cells were incubated in theCO₂ incubator for 24 hours with 0.25 mL of LPS in addition of 0.25 mL ofconcentrations of drugs or vehicle at the start of the incubation. Finalconcentration of LPS in the incubation medium was 1 μg/mL. After 24hours, the supernatant of each well by centrifugation at 1,700 rpm for10 minutes was stored at −80° C. until assay. TNF-alpha levels in themedium were measured by ELISA.

The IC₅₀ values of drugs on cytokine productions in LPS stimulated PBMCwere estimated by the regression analysis for the relative values ofcytokine level in the drug-treated wells compared to those of thevehicle-treated ones.

2. Test Results Example Compound name IC50 (nM) 1986-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2- <100methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoic acid

BEST MODE FOR CARRYING OUT THE INVENTION

The following examples are provided to further illustrate details forthe preparation of the compounds of the present invention. The examplesare not intended to be limitations on the scope of the instant inventionin any way, and they should not be so construed. Furthermore, thecompounds described in the following examples are not to be construed asforming the only genus that is considered as the invention, and anycombination of the compounds or their moieties may itself form a genus.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds.

The starting materials and intermediates are prepared by the applicationor adaptation of known methods, for example methods as described in theReference Examples or their obvious chemical equivalents.

The abbreviations, symbols and terms used in the Preparations, Examplesand Formulae have the following meanings.

DMF N,N-dimethylformamide

EtOAc or AcOEt Ethyl acetate

THF Tetrahydrofuran

Et3N Triethylamine

MeOH Methanol

EtOH Ethanol

BuOH Butanol

DCM Dichloromethane

Pd/C Palladium on carbon powder

Preparation 1

To a suspension of 2-pyridinethiol (17 g) in tetrahydrofuran (200 mL)was added triethylamine (15.5 g) in an ice-water bath under N₂. To thiswas added a solution of 4-cyanobenzoyl chloride (25.3 g) intetrahydrofuran (80 mL) below 10° C. over 30 minutes. After 15 minutes,the bath was removed and the mixture was stirred overnight at ambienttemperature. The mixture was concentrated in vacuo. The residue waspartitioned between chloroform and water. The organic layer was washedwith saturated sodium bicarbonate and brine, dried over magnesiumsulfate, and evaporated in vacuo. The residue (38 g) was triturated withisopropyl ether to give S-(2-pyridinyl) 4-cyanobenzenecarbothioate (325g) as a pale brown solid.

S-(2-Pyridinyl) 4-cyanobenzenecarbothioate

NMR (CDCl₃, δ): 7.38 (1H, t, J=7 Hz), 7.72 (1H, d, J=8 Hz), 7.75-7.87(3H, m), 8.11 (2H, d, J=8 Hz), 8.71 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 241 (M+H)

The following compound(s) was (were) obtained in substantially the samemanner as that of Preparation 1.

Preparation 2

S-(2-Pyridinyl) 2-chloro-4-pyridinecarbothioate

NMR (CDCl₃, δ): 7.40 (1H, m), 7.65-7.75 (2H, m), 7.75-7.90 (2H, m), 8.62(1H, d, J=5 Hz), 8.70 (1H, m)

Preparation 4

S-(2-Pyridinyl) 3-cyanobenzenecarbothioate

NMR (CDCl₃, δ): 7.39 (1H, m), 7.66 (1H, t, J=8 Hz), 7.72 (1H, t, J=8Hz), 7.83 (1H, m), 7.91 (1H, d, J=8 Hz), 8.24 (1H, d, J=8 Hz), 8.29 (1H,s), 8.71 (1H, m)

MS (ESI⁺): m/z 241 (M+H)

Preparation 5

S-(2-Pyridinyl) 3-methoxybenzenecarbothioate

NMR (CDCl₃, δ): 3.87 (3H, s), 7.16 (1H, m), 7.32-7.44 (2H, m), 7.51 (1H,m), 7.63 (1H, d, J=8 Hz), 7.71-7.83 (2H, m), 8.69 (1H, m)

Preparation 6

S-(2-Pyridinyl) 4-pyridinecarbothioate

NMR (CDCl₃, δ): 7.35-7.43 (1H, m), 7.73 (1H, d, J=8 Hz), 7.77-7.88 (3H,m), 8.70 (1H, d, J=7 Hz), 8.85 (2H, d, J=8 Hz)

MS (ESI⁺): m/z 217

Preparation 7

S-(2-Pyridinyl) 2-pyrazinecarbothioate

NMR (CDCl₃, δ): 7.38 (1H, m), 7.71 (1H, d, J=8 Hz), 7.82 (1H, m), 8.73(2H, m), 8.86 (1H, m), 9.17 (1H, s)

Preparation 8

S-(2-Pyridinyl) 3-pyridinecarbothioate

NMR (CDCl₃, δ): 7.37 (1H, m), 7.46 (1H, m), 7.73 (1H, m), 7.83 (1H, m),8.27 (1H, m), 8.68 (1H, m), 8.84 (1H, m), 9.23 (1H, m)

Preparation 9

To a solution of 2-ethyl-1H-pyrrole in toluene (120 mL) was addeddropwise 1M methylmagnesium bromide in tetrahydrofuran (170 mL) in a dryice-acetone bath below −60° C. over 30 minutes. Then the mixture wasstirred in an ice-water bath for 40 minutes. To this reaction mixturewas added S-(2-pyridinyl) 4-cyanobenzenecarbothioate (15.2 g)portionwise over 10 minutes in a dryice-acetone bath. After 1.5 hoursstirring, saturated ammonium chloride (100 mL) was added therein and thereaction mixture was allowed to ambient temperature. The mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with 1N sodium hydroxide (100 mL) twice, water, and brine, driedover magnesium sulfate, and evaporated in vacuo. The residue wastriturated with isopropyl ether to give4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (12.7 g) as a paleyellow solid.

4-[(5-Ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile

NMR (CDCl₃, δ): 1.32 (3H, t, J=8 Hz), 2.75 (2H, q, J=8 Hz), 6.11 (1H, d,J=5 Hz), 6.76 (1H, d, J=5 Hz), 7.77 (2H, d, J=8 Hz), 7.94 (2H, d, J=8Hz), 9.49 (1H, br s)

MS (ESI⁺): m/z 225 (M+H)

The following compound was obtained in substantially the same manner asthat of Preparation 9.

Preparation 10

(2E)-1-(5-Ethyl-1H-pyrrol-2-yl)-3-phenyl-2-propen-1-one

NMR (CDCl₃, δ): 1.31 (3H, t, J=7 Hz), 2.73 (2H, q, J=7 Hz), 6.10 (1H,m), 7.02 (1H, m), 7.27 (1H, d, J=16 Hz), 7.35-7.43 (3H, m), 7.63 (2H,m), 7.79 (1H, d, J=16 Hz)

MS (ESI⁺): m/z 226 (M+H)

Preparation 11

To a solution of 4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]-benzonitrile (12.5g) in N,N-dimethylformamide (63 mL) was added 60% sodium hydride in oil(2.68 g) in an ice-water bath under N₂. After 30 minutes, to the mixturewas added 1-(aminooxy)-2,4-dinitrobenzene (13.3 g). After 2 hours, themixture was partitioned between ethyl acetate and water. The aqueouslayer was extracted with ethyl acetate. The combined organic layer waswashed with water (100 mL) 3 times, 1N sodium hydroxide (100 mL), andbrine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by flash silica gel chromatography (silica gel, 500mL) eluted with hexane-chloroform=1-2, 1-5, and 1-10 followed bytriturated with isopropyl ether to give4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (8.1 g, 60.7%)as an yellow solid. The mixed fraction and the mother layer (7 g) wererepurified by flash silica gel chromatography (silica gel, 200 mL)eluted with hexane-chloroform=2-1 and 1-1 followed by triturated withisopropyl ether to give4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (2.0 g, 15%) asa pale yellow solid.

4-[(1-Amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-benzonitrile

NMR (CDCl₃, δ): 1.29 (3H, t, J=8 Hz), 2.77 (2H, q, J=8 Hz), 5.75 (2H, brs), 5.94 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.76 (2H, d, J=8 Hz),7.85 (2H, d, J=8 Hz)

MS (ESI⁺): m/z 240 (M+H)

The following compounds were obtained in substantially the same manneras that of Preparation 11.

Preparation 12

(1-Amino-5-ethyl-1H-pyrrol-2-yl)(2-chloro-4-pyridinyl)methanone

NMR (CDCl₃, δ): 1.29 (3H, t, J=7 Hz), 2.77 (2H, q, J=7 Hz), 5.71 (2H,s), 5.96 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.50 (1H, d, J=4 Hz),7.61 (1H, s), 8.52 (1H, d, J=4 Hz)

MS: (m/z) 250 (M+H)

Preparation 13

3-[(1-Amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-benzonitrile

NMR (CDCl₃, δ): 1.29 (3H, t, J=7 Hz), 2.77 (2H, q, J=7 Hz), 5.74 (2H,s), 5.94 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.59 (1H, t, J=8 Hz),7.82 (1H, d, J=8 Hz), 8.00 (1H, d, J=8 Hz), 8.06 (1H, s)

Preparation 14

(2E)-1-(1-Amino-5-ethyl-1H-pyrrol-2-yl)-3-phenyl-2-propen-1-one

NMR (CDCl₃, δ): 1.28 (3H, t, J=7 Hz), 2.73 (2H, q, J=7 Hz), 5.93 (1H, d,J=5 Hz), 6.99 (1H, d, J=5 Hz), 7.30 (1H, d, J=16 Hz), 7.37-7.43 (3H, m),7.62 (2H, m), 7.74 (1H, d, J=16 Hz)

MS (ESI⁺): m/z 241 (M+H)

Preparation 15

(1-Amino-5-ethyl-1H-pyrrol-2-yl)(3-methoxyphenyl)-methanone

NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 2.75 (2H, q, J=7 Hz), 3.86 (3H,s), 5.79 (2H, s), 5.89 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.07 (1H,m), 7.29-7.40 (3H, m)

MS (ESI⁺): m/z 245

Preparation 16

(1-Amino-5-ethyl-1H-pyrrol-2-yl)(4-pyridinyl)methanone

NMR (CDCl₃, δ): 1.29 (3H, t, J=7 Hz), 2.77 (2H, q, J=7 Hz), 5.76 (2H,s), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.58 (2H, d, J=7 Hz),8.75 (2H, d, J=7 Hz)

MS (ESI⁺): m/z 216

Preparation 17

(1-Amino-5-ethyl-1H-pyrrol-2-yl)(2-pyrazinyl)methanone

NMR (CDCl₃, δ): 1.29 (3H, t, J=7 Hz), 2.77 (2H, q, J=7 Hz), 5.79 (2H,s), 5.98 (1H, d, J=4 Hz), 7.27 (1H, d, J=4 Hz), 8.63 (1H, m), 8.71 (1H,m), 9.17 (1H, m)

Preparation 18

(1-Amino-5-ethyl-1H-pyrrol-2-yl)(3-pyridinyl)methanone

NMR (CDCl₃, δ): 1.29 (3H, t, J=7 Hz), 2.77 (2H, q, J=7 Hz), 5.78 (2H,s), 5.94 (1H, d, J=4 Hz), 6.65 (1H, d, J=4 Hz), 7.39 (1H, m), 8.06 (1H,m), 8.74 (1H, m), 8.99 (1H, m)

Preparation 19

(1-Amino-5-ethyl-1H-pyrrol-2-yl)(5-bromo-3-pyridinyl)-methanone

NMR (CDCl₃, δ): 1.29 (3H, t, J=7 Hz), 2.76 (2H, q, J=7 Hz), 5.72 (2H,s), 5.96 (1H, m), 6.65 (1H, m), 8.19 (1H, m), 8.70 (1H, m), 8.89 (1H, m)

Preparation 20

To a solution of tert-butyl 3-oxobutanoate (20.0 g) in tetrahydrofuran(200 mL) was added 60% sodium hydride in oil (556 g) portionwise over 20minutes in an ice-water bath under N₂. After 40 minutes, to the mixturewas added ethyl 5-iodopentanoate (35.6 g) at the temperature. After 15minutes, the mixture was stirred at ambient temperature. After 1 hour,the reaction mixture was heated at 50° C. for 24 hours. The cooledmixture was partitined between ethyl acetate and water. The aqueouslayer was extracted with ethyl acetate. The combined organic layer waswashed with water and brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by flash silica gelchromatography (silica gel, 1 L) eluting with hexane-ethyl acetate=50-1,20-1, 10-1, and 8-1 to give 1-tert-butyl 7-ethyl 2-acetylheptanedioate(27.3 g, 75.4%) as colorless oil.

1-tert-Butyl 7-ethyl 2-acetylheptanedioate

NMR (CDCl₃, δ): 1.20-1.38 (5H, m), 1.46 (9H, s), 1.54-1.71 (2H, m),1.75-1.87 (2H, m), 2.12 (3H, s), 2.30 (2H, t, J=8 Hz), 3.30 (12H, t, J=8Hz), 4.11 (2H, q, J=8 Hz)

The following compounds were obtained in substantially the same manneras that of Preparation 20.

Preparation 21

1-tert-Butyl 9-ethyl 2-acetylnonanedioate

NMR (CDCl₃, δ): 1.23-1.33 (9H, m), 1.46 (9H, s), 1.55 (2H, m), 1.77 (2H,m), 2.21 (3H, s), 2.28 (2H, t, J=7 Hz), 3.27 (1H, t, J=7 Hz), 4.12 (2H,q, J=7 Hz)

MS (ESI⁺): m/z 315 (M+H)

Preparation 22

tert-Butyl 2-acetylhexanoate

NMR (CDCl₃, δ): 0.90 (3H, t, J=8 Hz), 1.28-1.40 (4H, m), 1.46 (9H, s),1.73-1.89 (2H, m), 2.22 (3H, s), 3.30 (1H, t, J=8 Hz)

Preparation 23

1-tert-Butyl 8-ethyl 2-acetyloctanedioate

NMR (CDCl₃, δ): 1.21-1.33 (7H, m), 1.46 (9H, s), 1.54-1.69 (2H, m),1.74-1.85 (2H, m), 2.21 (3H, s), 2.28 (2H, t, J=8 Hz), 3.29 (1H, t, J=8Hz), 4.12 (2H, q, J=8 Hz)

Preparation 24

To a suspension of magnesium chloride (1.33 g) in dichloromethane (40mL) was added 1-tert-butyl 7-ethyl 2-acetylheptanedioate (4.0 g) atambient temperature under N₂.

To this mixture was added dropwise pyridine (2.26 mL) in an ice-waterbath. Then the mixture was stirred at ambient temperature for 40minutes. To the reaction mixture was added a solution of 3-cyanobenzoylchloride (3.01 g) in dichloromethane (6 mL) dropwise over 2 minutes. Thereaction mixture was stirred at ambient temperature for 2 hours. To themixture was added 1N hydrogen chloride and ethyl acetate in an ice-waterbath. The organic layer was washed with 1N hydrogen chloride, water, andbrine, dried over magnesium sulfate, and evaporated in vacuo to give asolid. The residue was purified by flash silica gel chromatography(silica gel, 300 mL) eluting with hexane-ethyl acetate=10-1, 8-1, 5-1,and 3-1 to give 1-tert-butyl 7-ethyl2-acetyl-2-(3-cyanobenzoyl)heptanedioate (4.23 g, 72.9%) as colorlessoil.

1-tert-Butyl 7-ethyl 2-acetyl-2-(3-cyanobenzoyl)-heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=8 Hz), 1.28-1.40 (11H, m), 1.63-1.75 (2H,m), 2.19-2.28 (2H, m), 2.32 (2H, t, J=8 Hz), 2.45 (3H, s), 4.11 (2H, q,J=8 Hz), 7.56 (1H, t, J=8 Hz), 7.80 (2H, dd, J=8, 1 Hz), 7.95 (2H, dd,J=8, 1 Hz), 8.06 (1H, br s)

MS (ESI⁺): m/z 416 (M+H)

The following compounds were obtained in substantially the same manneras that of Preparation 24.

Preparation 25

Ethyl 2-isobutyryl-4-methyl-3-oxopentanoate

NMR (300 MHz, CDCl₃, δ): 1.10-1.23 (12H, m), 1.30-1.43 (3H, m),2.91-3.10 (2H, m), 4.21-4.36 (2H, m)

Preparation 26

Ethyl 2-(2-chlorobenzoyl)-4-methyl-3-oxopentanoate

NMR (300 MHz, CDCl₃, δ): 0.79 (3H, t, J=75 Hz), 1.22 (6H, d, J=75 Hz),3.36-3.54 (1H, m), 3.88 (2H, q, J=75 Hz), 7.26-7.44 (4H, m)

Preparation 27

Ethyl 4-methyl-2-(2-naphthoyl)-3-oxopentanoate

NMR (300 MHz, CDCl₃, δ): 0.76-1.03 (3H, m), 1.10-1.30 (6H, m), 2.56-2.71(½H, m), 2.88-3.04 (⅙H, m), 3.20-3.35 (⅓H, m), 3.72-4.336 (3H, m),7.50-7.68 (2+⅓H, m), 7.82-8.01 (3+⅔H, m), 8.09 (⅓H, s), 8.35 (½H, s),8.41 (⅙H, s)

MS (ES+): m/e 313.45

Preparation 28

1-tert-Butyl 7-ethyl2-acetyl-2-[3-(trifluoromethyl)benzoyl]heptanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.32 (9H, s), 1.36-1.75 (4H, m),2.15-2.36 (4H, m), 2.45 (3H, s), 4.11 (2H, q, J=7 Hz), 7.56 (1H, t, J=8Hz), 7.79 (1H, d, J=8 Hz), 7.93 (1H, d, J=8 Hz), 8.04 (1H, s)

Preparation 29

1-tert-Butyl 7-ethyl2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.27-1.42 (2H, m), 1.34 (9H, s),1.65-1.77 (2H, m), 2.16-2.35 (4H, m), 2.39 (3H, s), 2.43 (3H, s), 4.10(2H, q, J=7 Hz), 7.87 (1H, s), 8.56 (1H, s), 8.73 (1H, s)

MS (ESI⁺): m/z 406 (M+H)

Preparation 30

1-tert-Butyl 7-ethyl2-(methoxyacetyl)-2-[(3-methoxy-5isoxazolyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.39 (9H, s), 1.35-1.50 (2H, m),1.64-1.75 (2H, m), 2.15-2.23 (2H, m), 2.32 (2H, t, J=7 Hz), 3.40 (3H,s), 4.01 (3H, s), 4.12 (2H, q, J=7 Hz), 4.57 (2H, s), 6.54 (1H, s)

Preparation 31

1-tert-Butyl 7-ethyl2-acetyl-2-[3-(1,3-oxazol-5-yl)benzoyl]heptanedioate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.33 (9H, s), 1.30-1.43 (2H, m),1.62-1.76 (2H, m), 2.17-2.35 (4H, m), 2.44 (3H, s), 4.09 (2H, q, J=7Hz), 7.42 (1H, s), 7.48 (1H, t, J=8 Hz), 7.69 (1H, d, J=8 Hz), 7.82 (1H,d, J=8 Hz), 7.94 (1H, s), 8.09 (1H, m)

Preparation 32

1-tert-Butyl 7-ethyl 2-acetyl-2-(3,4-dichlorobenzoyl)heptanedioate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.35 (9H, s),1.63-1.74 (2H, m), 2.15-2.34 (4H, m), 2.41 (3H, s), 4.10 (2H, q, J=7Hz), 7.48 (1H, d, J=8 Hz), 7.56 (1H, dd, J=2, 8 Hz), 7.88 (1H, d, J=2Hz)

Preparation 33

1-tert-Butyl 7-ethyl2-acetyl-2-[(4-chloro-2-pyridinyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.23-1.30 (3H, m), 1.25 (9H, s), 1.40-1.58 (2H, m),1.65-1.77 (2H, m), 2.10-2.21 (2H, m), 2.35 (2H, t, J=7 Hz), 2.61 (3H,s), 4.12 (2H, q, J=7 Hz), 7.39 (1H, m), 8.04 (1H, m), 8.43 (1H, d, J=5Hz)

MS (ESI⁺): m/z 426 (M+H)

Preparation 34

1-tert-Butyl 7-ethyl2-[(5-chloro-2-thienyl)carbonyl]-2-(methoxyacetyl)heptanedioate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.25-1.40 (2H, m), 1.41 (9H, s),1.62-1.74 (2H, m), 2.26-2.37 (4H, m), 3.37 (3H, s), 4.11 (2H, q, J=7Hz), 4.30 (1H, d, J=17 Hz), 4.42 (1H, d, J=17 Hz), 6.92 (1H, d, J=4 Hz),7.39 (1H, d, J=4 Hz)

Preparation 35

1-tert-Butyl 7-ethyl2-acetyl-2-[(6-methoxy-2-pyrazinyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.26 (9H, s), 1.38-1.49 (2H, m),1.66-1.80 (2H, m), 2.14-2.26 (2H, m), 2.33 (2H, t, J=7 Hz), 2.57 (3H,s), 3.90 (3H, s), 4.12 (2H, q, J=7 Hz), 8.37 (1H, s), 8.83 (1H, s)

Preparation 36

1-tert-Butyl 7-ethyl 2-acetyl-2-(1-benzofuran-2-ylcarbonyl)heptanedioate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.33 (9H, s), 1.38-1.55 (2H, m),1.64-1.77 (2H, m), 2.23-2.36 (4H, m), 2.49 (3H, s), 4.08 (2H, q, J=7Hz), 7.32 (1H, m), 7.46 (2H, m), 7.54 (1H, s), 7.71 (1H, d, J=8 Hz)

Preparation 37

1-tert-Butyl 7-ethyl 2-acetyl-2-(1-benzothien-2-ylcarbonyl)heptanedioate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.30-1.45 (2H, m), 1.39 (9H, s),1.62-1.75 (2H, m), 2.25-2.38 (4H, m), 2.40 (3H, s), 4.10 (2H, q, J=7Hz), 7.36-7.51 (2H, m), 7.76 (1H, s), 7.82-7.88 (2H, m)

Preparation 38

1-tert-Butyl 7-ethyl 2-acetyl-2-(1,3-oxazol-5-ylcarbonyl)heptanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.30-1.45 (2H, m), 1.38 (9H, s),1.63-1.77 (2H, m), 2.15-2.27 (2H, m), 2.30 (2H, t, J=7 Hz), 2.43 (3H,s), 4.10 (2H, q, J=7 Hz), 7.80 (1H, s), 7.93 (1H, s)

Preparation 39

1-tert-Butyl 7-ethyl 2-acetyl-2-benzoylheptanedioate

NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.20-1.40 (2H, m), 1.32 (9H, s),1.60-1.73 (2H, m), 2.26-2.38 (4H, m), 2.40 (3H, s), 4.12 (2H, q, J=7Hz), 7.36-7.78 (5H, m)

Preparation 40

1-tert-Butyl 7-ethyl 2-acetyl-2-(6-quinolinylcarbonyl)heptanedioate

NMR (CDCl₃, δ): 1.21 (3H, t, J=7 Hz), 1.30 (9H, s), 1.32-1.47 (2H, m),1.64-1.77 (2H, m), 2.26-2.38 (4H, m), 2.46 (3H, s), 4.08 (2H, q, J=7Hz), 7.48 (1H, m), 8.04 (1H, dd, J=2 Hz, 8 Hz), 8.13 (1H, d, J=8 Hz),8.23 (1H, d, J=8 Hz), 8.28 (1H, d, J=2 Hz), 9.00 (1H, m)

MS (ESI⁺): m/z 442 (M+H)

Preparation 41

1-tert-Butyl 9-ethyl2-acetyl-2-[4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoyl]-nonanedioate

NMR (CDCl₃, δ): 1.23-1.37 (11H, m), 1.60 (9H, s), 2.15-2.31 (4H, m),2.46 (3H, s), 4.12 (2H, q, J=7 Hz), 5.10 (2H, s), 7.26-7.40 (5H, m),7.65 (1H, s, br), 7.84 (2H, d, J=9 Hz), 8.06 (2H, d, J=9 Hz)

Preparation 42

1-tert-Butyl 7-ethyl 2-acetyl-2-(2-chloroisonicotinoyl)heptanedioate

NMR (CDCl₃, δ): 1.20-1.40 (14H, m), 1.61-1.75 (2H, m), 2.19-2.28 (2H,m), 2.20 (2H, t, J=8 Hz), 2.31 (2H, t, J=8 Hz), 2.46 (3H, s), 4.11 (2H,q, J=8 Hz), 7.41 (1H, dd, J=7, 1 Hz), 7.55 (1H, d, J=1 Hz), 8.50 (1H, d,J=7 Hz)

Preparation 43

1-tert-Butyl 7-ethyl 2-acetyl-2-[3-(methylsulfonyl)benzoyl]heptanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=8 Hz), 1.27-1.40 (11H, m), 1.61-1.75 (2H,m), 2.19-2.35 (4H, m), 2.46 (3H, s), 3.07 (3H, s), 4.10 (2H, q, J=8 Hz),7.65 (1H, t, J=8 Hz), 7.99 (1H, dd, J=8, 1 Hz), 8.09 (2H, br d, J=8 Hz),8.34 (1H, br s)

Preparation 44

1-tert-Butyl 7-ethyl 2-acetyl-2-(3-nitrobenzoyl)heptanedioate

NMR (CDCl₃, δ): 1.30-1.39 (12H, m), 1.61-1.75 (2H, m), 2.19-2.35 (4H,m), 2.47(3H, s), 4.10 (2H, q, J=8 Hz), 7.63 (1H, t, J=8 Hz), 8.09 (1H,br d, J=8 Hz), 8.39 (1H, br d, J=8 Hz), 8.60 (11H, br s)

Preparation 45

tert-Butyl 2-acetyl-2-(4-cyanobenzoyl)hexanoate

NMR (CDCl₃, δ): 0.90 (3H, t, J=8 Hz), 1.20-1.44 (13H, m), 2.15-2.25 (2H,m), 2.45 (3H, s), 7.70 (2H, d, J=8 Hz), 7.83 (2H, d, J=8 Hz)

Preparation 46

1-tert-Butyl 7-ethyl2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.36 (9H, s), 1.32-1.45 (2H, m),1.65-1.77 (2H, m), 2.18-2.28 (2H, m), 2.32 (2H, t, J=7 Hz), 2.45 (3H,s), 4.11 (2H, q, J=7 Hz), 8.20 (1H, m), 8.80 (2H, m)

MS: (m/z) 470, 472 (M+H)

Preparation 47

1-tert-Butyl 7-ethyl2-(2-chloroisonicotinoyl)-2-[(methylthio)acetyl]heptanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.37 (9H, s), 1.23-1.45 (2H, m),1.63-1.77 (2H, m), 2.05 (3H, s), 2.16-2.28 (2H, m), 2.32 (2H, t, J=7Hz), 3.16 (1H, d, J=17 Hz), 4.07 (1H, d, J=17 Hz), 4.11 (2H, q, J=7 Hz),7.68 (1H, d, J=5 Hz), 7.87 (1H, s), 8.49 (1H, d, J=5 Hz)

Preparation 48

Ethyl 2-(4-fluorobenzoyl)-3-oxobutanoate

NMR (CDCl₃, δ): (mixture of tautomers) 0.97 and 1.02 (3H, t, J=7 Hz),2.07 and 2.42 (3H, s), 4.01 and 4.13 (2H, q, J=7 Hz), 7.06-7.18, 7.56,and 7.85 (4H, m)

MS (ESI⁺): m/z 275 (M+H)

Preparation 49

1-tert-Butyl 8-ethyl 2-acetyl-2-(3-cyanobenzoyl)octanedioate

NMR (CDCl₃, δ): 1.21-1.46 (16H, m), 1.56-1.70 (2H, m), 2.15-2.25 (2H,m), 2.29 (2H, t, J=8 Hz), 2.45 (3H, s), 4.12 (2H, q, J=8 Hz), 7.56 (1H,t, J=8 Hz), 7.80 (2H, dd, J=8, 1 Hz), 7.95 (2H, dd, J=8, 1 Hz), 8.05(1H, br s)

Preparation 50

1-tert-Butyl 7-ethyl2-acetyl-2-[(6-chloro-2-pyridinyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.27 (9H, s), 1.20-1.78 (4H, m),2.08 (2H, t, J=7 Hz), 2.26-2.40 (2H, m), 2.69 (3H, s), 4.12 (2H, q, J=7Hz), 7.43 (1H, d, J=8 Hz), 7.81 (1H, t, J=8 Hz), 7.96 (1H, d, J=8 Hz)

MS (ESI⁺): m/z 426

Preparation 51

1-tert-Butyl 7-ethyl 2-acetyl-2-(3-methoxybenzoyl)heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, m), 1.34 (9H, s), 1.20-1.92 (4H, m), 2.10-2.38(4H, m), 2.41 (3H, s), 3.84 (3H, s), 4.04-4.22 (2H, m), 7.08 (1H, br),7.23-7.40 (3H, m)

Preparation 52

1-tert-Butyl 7-ethyl 2-acetyl-2-(3,5-dichlorobenzoyl)heptanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.26-1.40 (2H, m), 1.36 (9H, s),1.63-1.76 (2H, m), 2.15-2.36 (4H, m), 2.43 (3H, s), 4.10 (2H, q, J=7Hz), 7.51 (1H, m), 7.60 (2H, m)

Preparation 53

1-tert-Butyl 7-ethyl2-acetyl-2-[(5-chloro-2-thienyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.40 (9H, s), 1.30-1.90 (4H, m),2.20-2.35 (4H, m), 2.38 (3H, s), 4.11 (2H, q, J=7 Hz), 6.91 (1H, d, J=4Hz), 7.32 (1H, d, J=4 Hz)

Preparation 54

1-tert-Butyl 7-ethyl 2-acetyl-2-(3-fluorobenzoyl)heptanedioate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.35 (9H, s), 1.35-1.45 (2H, m),1.64-1.74 (2H, m), 2.16-2.35 (4H, m), 2.42 (3H, s), 4.09 (2H, q, J=7Hz), 7.24 (1H, m), 7.35-7.43 (1H, m), 7.46-7.53 (2H, m)

Preparation 55

1-tert-Butyl 7-ethyl 2-acetyl-2-(3-quinolinylcarbonyl)heptanedioate

NMR (CDCl₃, δ): 1.22 (3H, t, J=7 Hz), 1.33 (9H, s), 1.33-1.53 (2H, m),1.65-1.78 (2H, m), 2.25-2.43 (4H, m), 2.47 (3H, s), 4.08 (2H, q, J=7Hz), 7.63 (1H, t, J=8 Hz), 7.81-7.87 (1H, t, J=8 Hz), 7.91 (1H, d, J=8Hz), 8.56 (1H, m), 9.24 (1H, m)

MS (ESI⁺): m/z 442

Preparation 56

1-tert-Butyl 7-ethyl 2-acetyl-2-isonicotinoylheptanedioate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.31 (9H, s), 1.30-1.45 (2H, m),1.65-1.76 (2H, m), 2.18-2.28 (2H, m), 2.31 (2H, t, J=7 Hz), 2.45 (3H,s), 4.10 (2H, q, J=7 Hz), 7.52 (2H, d, J=7 Hz), 8.75 (2H, d, J=7 Hz)

Preparation 57

1-tert-Butyl 7-ethyl2-acetyl-2-[(3-methoxy-5-isoxazolyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.39 (9H, s), 1.35-1.50 (2H, m),1.62-1.75 (2H, m), 2.11-2.23 (2H, m), 2.33 (2H, t, J=7 Hz), 2.49 (3H,s), 4.01 (3H, s), 4.11 (2H, q, J=7 Hz), 6.53 (1H, s)

Preparation 58

1-tert-Butyl 7-ethyl2-acetyl-2-[(5-methyl-3-isoxazolyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.31-1.48 (2H, m), 1.37 (9H, s),1.63-1.75 (2H, m), 2.18-2.26 (2H, m), 2.31 (2H, t, J=7 Hz), 2.47 (3H,s), 2.50 (3H, s), 4.11 (2H, q, J=7 Hz), 6.38 (1H, s)

Preparation 59

1-tert-Butyl 7-ethyl2-(2-chloroisonicotinoyl)-2-(methoxyacetyl)heptanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.32-1.45 (2H, m), 1.36 (9H, s),1.64-1.78 (2H, m), 2.16-2.28 (2H, m), 2.31 (2H, t, J=7 Hz), 3.36 (3H,s), 4.11 (2H, q, J=7 Hz), 4.25 (1H, d, J=17 Hz), 4.39 (1H, d, J=17 Hz),7.39 (1H, d, J=5 Hz), 7.54 (1H, s), 8.50 (1H, d, J=5 Hz)

MS (ESI⁺): m/z 456

Preparation 60

1-tert-Butyl 7-ethyl 2-(methoxyacetyl)-2-(3-methoxybenzoyl)heptanedioate

NMR (CDCl₃, δ): 1.22 (3H, t, J=7 Hz), 1.25-1.33 (2H, m), 1.34 (9H, s),1.60-1.75 (2H, m), 2.15-2.40 (4H, m), 3.38 (3H, s), 3.83 (3H, s), 4.08(2H, q, J=7 Hz), 4.39 (1H, d, J=17 Hz), 4.55 (1H, d, J=17 Hz), 7.07 (1H,m), 7.26-7.34 (3H, m)

MS (ESI⁺): m/z 451

Preparation 61

1-tert-Butyl 7-ethyl2-(methoxyacetyl)-2-(6-quinolinylcarbonyl)heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.32 (9H, s), 1.30-1.50 (2H, m),1.65-1.78 (2H, m), 2.26-2.44 (4H, m), 3.38 (3H, s), 4.11 (2H, q, J=7Hz), 4.38 (1H, d, J=17 Hz), 4.57 (1H, d, J=17 Hz), 7.47 (1H, m), 8.03(1H, d, J=8 Hz), 8.13 (1H, d, J=8 Hz), 8.28 (1H, d, J=8 Hz), 8.27 (1H,s), 9.01 (1H, m)

MS (ESI⁺): m/z 472

Preparation 62

1-tert-Butyl 7-ethyl2-(methoxyacetyl)-2-(3-pyridinylcarbonyl)heptanedioate

NMR (CDCl₃, δ): 1.23 (3H, 1, J=7 Hz), 1.30-1.47 (2H, m), 1.35 (9H, s),1.63-1.78 (2H, m), 2.22-2.38 (4H, m), 3.37 (3H, s), 4.10 (2H, q, J=7Hz), 4.32 (1H, d, J=17 Hz), 4.45 (1H, d, J=17 Hz), 7.37 (1H, m), 8.03(1H, m), 8.73 (1H, m), 8.92 (1H, m)

Preparation 63

1-tert-Butyl 7-ethyl 2-(3-chlorobenzoyl)-2-(methoxyacetyl)heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.35 (9H, s), 1.20-1.50 (2H, m),1.60-1.73 (2H, m), 2.25-2.35 (4H, m), 3.37 (3H, s), 4.12 (2H, q, J=7Hz), 4.35 (1H, d, J=17 Hz), 4.50 (1H, d, J=17 Hz), 7.34 (1H, m), 7.48(1H, d, J=8 Hz), 7.59 (1H, d, J=8 Hz), 7.73 (1H, m)

Preparation 64

1-tert-Butyl 7-ethyl 2-acetyl-2-(3-methylbenzoyl)heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.30-1.40 (2H, m), 1.33 (9H, s),1.60-1.72 (2H, m), 2.10-2.38 (4H, m), 2.21 (3H, s), 2.39 (3H, s), 4.10(2H, q, J=7 Hz), 7.26-7.36 (2H, m), 7.48-7.62 (2H, m)

MS (ESI⁺): m/z 405

Preparation 67

1-tert-Butyl 7-ethyl2-(methoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.36 (9H, s), 1.30-1.45 (2H, m),1.62-1.76 (2H, m), 2.20-2.36 (4H, m), 2.40 (3H, s), 3.38 (3H, s), 4.10(2H, q, J=7 Hz), 4.34 (1H, d, J=17 Hz), 4.49 (1H, d, J=17 Hz), 7.86 (1H,s), 8.56 (1H, s), 8.73 (1H, s)

MS (ESI⁺): m/z 436

Preparation 68

1-tert-Butyl 7-ethyl2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.36 (9H, s), 1.32-1.45 (2H, m),1.65-1.77 (2H, m), 2.18-2.28 (2H, m), 2.32 (2H, t, J=7 Hz), 2.45 (3H,s), 4.11 (2H, q, J=7 Hz), 8.20 (1H, m), 8.80 (2H, m)

MS (ESI⁺): m/z 470, 472

Preparation 69

1-tert-Butyl 7-ethyl2-[(5-bromo-3-pyridinyl)carbonyl]-2-(methoxyacetyl)heptanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.30-1.44 (2H, m), 1.37 (9H, s),1.65-1.77 (2H, m), 2.18-2.36 (4H, m), 3.36 (3H, s), 4.10 (2H, q, J=7Hz), 4.28 (1H, d, J=17 Hz), 4.40 (1H, d, J=17 Hz), 8.18 (1H, m), 8.80(2H, m)

MS (ESI⁺): m/z 500, 502

Preparation 70

1-tert-Butyl 7-ethyl2-acetyl-2-[(5,6-dichloro-3-pyridinyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.25-1.40 (2H, m), 1.38 (9H, s),1.65-1.75 (2H, m), 2.18-2.27 (2H, m), 2.28-2.37 (2H, m), 2.44 (3H, s),4.12 (2H, q, J=7 Hz), 8.13 (1H, d, J=2 Hz), 8.57 (1H, d, J=2 Hz)

Preparation 71

1-tert-Butyl 6-ethyl2-(methoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.36 (9H, s), 1.60-1.80 (2H, m),2.20-2.45 (4H, m), 2.39 (3H, s), 3.38 (3H, s), 4.12 (2H, q, J=7 Hz),4.38 (1H, d, J=18 Hz), 4.50 (1H, d, J=18 Hz), 7.87 (1H, s), 8.55 (1H,s), 8.73 (1H, s)

MS (ESI⁺): m/z 422

Preparation 72

1-tert-Butyl 5-ethyl2-(methoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.37 (9H, s), 2.23-2.70 (4H, m),2.39 (3H, s), 3.37 (3H, s), 4.12 (2H, q, J=7 Hz), 4.32 (1H, d, J=18 Hz),4.43 (1H, d, J=18 Hz), 7.84 (1H, s), 8.55 (1H, s), 8.73 (1H, s)

MS (ESI⁺): m/z 408

Preparation 73

1-tert-Butyl 6-ethyl2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.34 (9H, s), 1.60-1.75 (2H, m),2.20-2.39 (4H, m), 2.39 (3H, s), 2.46 (3H, s), 4.11 (2H, q, J=7 Hz),7.87 (1H, s), 8.56 (1H, s), 8.73 (1H, s)

MS (ESI⁺): m/z 392

Preparation 74

1-tert-Butyl 5-ethyl2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.36 (9H, s), 2.39 (3H, s), 2.44(3H, s), 2.35-2.47 (2H, m), 2.56-2.70 (2H, m), 4.11 (2H, q, J=7 Hz),7.88 (1H, s), 8.56 (1H, s), 8.74 (1H, s)

MS (ESI⁺): m/z 378

Preparation 75

1-tert-Butyl 5-ethyl2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]pentanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.37 (9H, s), 2.40 (2H, t, J=7Hz), 2.59 (2H, t, J=7 Hz), 2.46 (3H, s), 4.13 (2H, q, J=7 Hz), 8.20 (1H,t, J=3 Hz), 8.81 (2H, dd, J=7, 3 Hz)

Preparation 76

1-tert-Butyl 7-ethyl 2-(3-cyanobenzoyl)-2-(methoxyacetyl)heptanedioate

NMR (CDCl₃, δ): 1.20-1.41 (14H, m), 1.60-1.74 (2H, m), 2.27-2.34 (4H,m), 3.37 (83H, s), 4.10 (2H, q, J=8 Hz), 4.29 (1H, d, J=16 Hz), 4.46(1H, d, J=16 Hz), 7.55 (1H, t, J=8 Hz), 7.80 (1H, dd, J=8, 1 Hz), 7.93(1H, dd, J=8, 1 Hz), 8.04 (1H, br s)

Preparation 77

1-tert-Butyl 7-ethyl2-[(acetyloxy)acetyl]-2-[(5-bromo-3-pyridinyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.22-1.28 (5H, m), 1.36 (9H, s), 1.68 (2H, m), 2.14 (3H,s), 2.32 (2H, m), 4.11 (2H, q, J=7 Hz), 5.07 (1H, d, J=18 Hz), 5.34 (1H,d, J=18 Hz), 8.21 (1H, m), 8.81 (2H, m)

Preparation 78

To 1-tert-butyl 7-ethyl 2-acetyl-2-(3-cyanobenzoyl)-heptanedioate (4.2g) was added trifluoroacetic acid (20 mL) in an ice-water bath. After 30minutes, the bath was removed and the reaction mixture was stirred atambient temperature. After 1 hour, the mixture was concentrated. Theresidue was dissolved in toluene and was evaporated in vacuo to giveethyl 6-(3-cyanobenzoyl)-7-oxooctanoate (3.20 g, 100.4%) as colorlessoil.

Ethyl 6-(3-cyanobenzoyl)-7-oxooctanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=8 Hz), 1.28-1.40 (2H, m), 1.60-1.74 (2H,m), 1.91-2.14 (2H, m), 2.17 (3H, s), 2.31 (2H, t, J=8 Hz), 4.11 (2H, q,J=8 Hz), 4.39 (1H, t, J=8 Hz), 7.64 (1H, t, J=8 Hz), 7.87 (2H, dd, J=8,1 Hz), 8.20 (2H, dd, J=8, 1 Hz), 8.26 (1H, br s)

MS (ESI⁻): m/z 314 (M−H)

The following compounds were obtained in substantially the same manneras that of Preparation 78.

Preparation 79

Ethyl 7-oxo-6-[3-(trifluoromethyl)benzoyl]octanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.32-1.43 (2H, m), 1.62-1.77 (2H,m), 1.96-2.17 (2H, m), 2.17 (3H, s), 2.30 (2H, t, J=7 Hz), 4.11 (2H, q,J=7 Hz), 4.44 (1H, t, J=7 Hz), 7.64 (1H, t, J=8 Hz), 7.86 (1H, d, J=8Hz), 8.15 (1H, d, J=8 Hz), 8.24 (1H, s)

Preparation 80

Ethyl 6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.27-1.44 (2H, m), 1.65-1.75 (2H,m), 1.90-2.12 (2H, m), 2.17 (3H, s), 2.25-2.34 (2H, m), 2.43 (3H, s),4.10 (2H, q, J=7 Hz), 4.42 (1H, t, J=7 Hz), 8.03 (1H, s), 8.63 (1H, s),8.98 (1H, s)

MS (ESI⁺): m/z 306 (M+H)

Preparation 81

Ethyl 8-methoxy-6-[(3-methoxy-5-isoxazolyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.34-1.47 (2H, m), 1.65-1.74 (2H,m), 1.83-2.03 (2H, m), 2.29 (2H, t, J=7 Hz), 3.31 (3H, s), 4.05 (5H, s),4.11 (2H, q, J=7 Hz), 4.51 (1H, t, J=7 Hz), 6.56 (1H, s)

MS (ESI⁺): m/z 342 (M+H)

Preparation 82

Ethyl 6-[3-(1,3-oxazol-5-yl)benzoyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.33-1.46 (2H, m), 1.63-1.77 (2H,m), 1.95-2.17 (2H, m), 2.17 (3H, s), 2.30 (2H, t, J=7 Hz), 4.12 (2H, q,J=7 Hz), 4.46 (1H, t, J=7 Hz), 7.47 (1H, s), 7.56 (1H, t, J=8 Hz),7.85-7.96 (2H, m), 7.98 (1H, s), 8.27 (1H, m)

Preparation 83

Ethyl 6-(3,4-dichlorobenzoyl)-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.60-1.74 (2H,m), 1.91-2.14 (2H, m), 2.14 (3H, s), 2.30 (2H, t, J=7 Hz), 4.11 (2H, q,J=7 Hz), 4.34 (1H, t, J=7 Hz), 7.57 (1H, d, J=8 Hz), 7.78 (1H, dd, J=2,8 Hz), 8.06 (1H, d, J=2 Hz)

Preparation 84

Ethyl 6-[(4-chloro-2-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.34-1.48 (2H, m), 1.62-1.77 (2H,m), 1.80-2.10 (2H, m), 2.31 (2H, t, J=7 Hz), 2.34 (3H, s), 4.12 (2H, q,J=7 Hz), 4.83-4.92 (1H, m), 7.49 (1H, dd, J=2 Hz, 5 Hz), 8.04 (1H, d,J=2 Hz), 8.57 (1H, d, J=5 Hz)

MS (ESI⁺): m/z 326 (M+H)

Preparation 85

Ethyl 6-[(5-chloro-2-thienyl)carbonyl]-8-methoxy-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.32-1.42 (2H, m), 1.60-1.73 (2H,m), 1.84-2.06 (2H, m), 2.28 (2H, t, J=7 Hz), 3.30 (3H, s), 3.97 (1H, d,J=17 Hz), 4.06 (1H, d, J=17 Hz), 4.11 (2H, q, J=7 Hz), 4.40 (1H, t, J=7Hz), 6.99 (1H, d, J=4 Hz), 7.56 (1H, d, J=4 Hz)

Preparation 86

Ethyl 6-[(6-methoxy-2-pyrazinyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.34-1.48 (2H, m), 1.60-1.78 (2H,m), 1.88-2.08 (2H, m), 2.31 (3H, s), 2.32 (2H, t, J=7 Hz), 4.01 (3H, s),4.11 (2H, q, J=7 Hz), 4.62 (1H, t, J=7 Hz), 8.44 (1H, s), 8.81 (1H, s)

MS (ESI⁺): m/z 323 (M+H)

Preparation 87

Ethyl 6-(1-benzofuran-2-ylcarbonyl)-7-oxooctanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.34-1.48 (2H, m), 1.62-1.76 (2H,m), 1.93-2.19 (2H, m), 2.24 (3H, s), 2.30 (2H, t, J=7 Hz), 4.10 (2H, q,J=7 Hz), 4.37 (1H, t, J=7 Hz), 7.34 (1H, t, J=8 Hz), 7.51 (1H, t, J=8Hz), 7.56-7.65 (2H, m), 7.73 (1H, d, J=8 Hz)

MS (ESI⁺): m/z 895 (M+H)

Preparation 88

Ethyl 6-(1-benzothien-2-ylcarbonyl)-7-oxooctanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.35-1.48 (2H, m), 1.60-1.80 (2H,m), 1.95-2.17 (2H, m), 2.19 (3H, s), 2.30 (2H, t, J=7 Hz), 4.10 (2H, q,J=7 Hz), 4.36 (1H, t, J=7 Hz), 7.38-7.53 (2H, m), 7.82-7.93 (2H, m),8.05 (1H, s)

Preparation 89

Ethyl 6-(1,3-oxazol-5-ylcarbonyl)-7-oxooctanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.65-1.78 (2H,m), 1.92-2.10 (2H, m), 2.21 (3H, s), 2.32 (2H, t, J=7 Hz), 4.11 (3H, m),7.88 (1H, s), 8.05 (1H, s)

Preparation 90

Ethyl 6-benzoyl-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.29-1.42 (2H, m), 1.60-1.75 (2H,m), 1.92-2.12 (2H, m), 2.14 (3H, s), 2.29 (2H, t, J=7 Hz), 4.10 (2H, q,J=7 Hz), 4.43 (1H, t, J=7 Hz), 7.42-7.53 (2H, m), 7.55-7.64 (1H, m),7.98 (2H, d, J=8 Hz)

Preparation 91

Ethyl 7-oxo-6-(6-quinolinylcarbonyl)octanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.36-1.48 (2H, m), 1.65-1.78 (2H,m), 2.00-2.18 (2H, m), 2.18 (3H, s), 2.30 (2H, t, J=7 Hz), 4.10 (2H, q,J=7 Hz), 4.58 (1H, t, J=8 Hz), 7.54 (1H, m), 8.18 (1H, d, J=8 Hz), 8.28(1H, dd, J=2 Hz, 8 Hz), 8.32 (1H, d, J=8 Hz), 8.51 (1H, d, J=2 Hz), 9.05(1H, m)

MS (ESI⁺): m/z 342 (M+H)

Preparation 92

Ethyl 8-[4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoyl]-9-oxodecanoate

NMR (CDCl₃, δ): 1.23-1.37 (9H, m), 1.55-1.68 (1H, s), 2.01 (2H, m), 2.18(3H, s), 2.29 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.39 (1H, t, J=7Hz), 5.11 (2H, s), 7.30-7.49 (5H, m), 7.74 (1H, s, br), 8.04-8.13 (4H,m)

MS (ESI⁻): m/z 530 (M−H)

Preparation 93

Ethyl 7-(1,3-oxazol-5-yl)-7-oxoheptanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.41 (2H, m), 1.76 (2H, m), 2.03(2H, m), 2.31 (2H, m), 3.20 (2H, m), 4.10 (2H, q, J=7 Hz), 7.94 (1H, s),8.10 (1H, s)

Preparation 94

Ethyl 6-[3-(methylsulfonyl)benzoyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=8 Hz), 1.59-1.64 (2H, m), 1.91-2.15 (2H,m), 2.18 (3H, s), 2.30 (2H, t, J=8 Hz), 3.11 (3H, s), 4.10 (2H, q, J=8Hz), 4.45 (1H, t, J=8 Hz), 7.23 (1H, t, J=8 Hz), 8.17 (1H, dd, J=8, 1Hz), 8.25 (2H, br d, J=8 Hz), 8.53 (1H, br s)

MS (ESI⁺): m/z 369 (M+H)

Preparation 95

Ethyl 6-(2-chloroisonicotinoyl)-7-oxooctanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=8 Hz), 1.30-1.40 (2H, m), 1.60-1.71 (2H,m), 1.90-2.14 (2H, m), 2.27 (3H, s), 2.25-2.74 (2H, m), 4.11 (2H, q, J=8Hz), 4.32 (1H, t, J=8 Hz), 7.15 (1H, dd, J=7, 1 Hz), 7.76 (1H, d, J=1Hz), 8.09 (1H, d, J=7 Hz)

MS (ESI⁺): m/z 326 (M+H)

Preparation 96

Ethyl 6-(3-nitrobenzoyl)-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=8 Hz), 1.29-1.41 (2H, m), 1.60-1.74 (2H,m), 1.91-2.16 (2H, m), 2.19 (3H, s), 2.30 (2H, t, J=8 Hz), 4.11 (2H, q,J=8 Hz), 4.46 (1H, t, J=8 Hz), 7.71 (1H, t, J=8 Hz), 8.30 (1H, br d, J=8Hz), 8.45 (4H, br d, J=8 Hz), 8.80 (1H, br s)

MS (ESI⁺): m/z 337 (M+H)

Preparation 97

4-(2-Acetylhexanoyl)benzonitrile

NMR (CDCl₃, δ): 0.90 (3H, t, J=8 Hz), 1.18-1.44 (4H, m), 1.90-2.12 (2H,m), 2.17 (3H, s), 4.40 (1H, t, J=8 Hz), 7.80 (2H, d, J=8 Hz), 8.08 (2H,d, J=8 Hz)

MS (ESI⁻): m/z 242 (M−H)

Preparation 98

Ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.32-1.43 (2H, m), 1.60-1.76 (2H,m), 1.96-2.15 (2H, m), 2.19 (3H, s), 2.30 (2H, t, J=7 Hz), 4.12 (2H, q,J=7 Hz), 4.36 (1H, t, J=7 Hz), 8.37 (1H, s), 8.87 (1H, br), 9.07 (1H,br)

MS: (m/z) 370, 372 (M+H)

Preparation 99

Ethyl 6-(2-chloroisonicotinoyl)-8-(methylthio)-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.34-1.47 (2H, m), 1.60-1.77 (2H,m), 1.92 (3H, s), 1.93-2.05 (2H, m), 2.30 (2H, t, J=7 Hz), 3.19 (1H, d,J=17 Hz), 3.26 (1H, d, J=17 Hz), 4.11 (2H, q, J=7 Hz), 4.68 (1H, t, J=7Hz), 7.72 (1H, d, J=5 Hz), 7.86 (1H, s), 8.57 (1H, d, J=5 Hz)

MS: (m/z) 370 (M−H), 372 (M+H)

Preparation 100

Ethyl 7-(3-cyanobenzoyl)-8-oxononanoate

NMR (CDCl₃, δ): 1.21-1.44 (7H, m), 1.55-1.69 (2H, m), 1.89-2.15 (2H, m),2.17 (3H, s), 2.29 (2H, t, J=8 Hz), 4.12 (2H, q, J=8 Hz), 4.39 (1H, t,J=8 Hz), 7.64 (1H, t, J=8 Hz), 7.87 (1H, dd, J=8, 1 Hz), 8.20 (1H, dd,J=8, 1 Hz), 8.27 (1H, br s)

MS (ESI⁺): m/z 330 (M+H)

Preparation 101

Ethyl 6-[(6-chloro-2-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.36-1.52 (2H, m), 1.63-1.75 (2H,m), 1.77-2.06 (2H, m), 2.29 (2H, t, J=7 Hz), 2.45 (3H, s), 4.12 (2H, q,J=7 Hz), 4.82 (1H, t, J=7 Hz), 7.51 (1H, d, J=8 Hz), 7.82 (1H, t, J=8Hz), 7.97 (1H, d, J=8 Hz)

MS (ESI⁺): m/z 326

Preparation 102

Ethyl 6-(3-methoxybenzoyl)-7-oxooctanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.60-1.77 (2H,m), 1.92-2.12 (2H, m), 2.15 (3H, s), 2.31 (2H, t, J=7 Hz), 3.88 (3H, s),4.12 (2H, q, J=7 Hz), 4.42 (1H, t, J=7 Hz), 7.14 (1H, dd, J=2 Hz, 8 Hz),7.40 (1H, t, J=8 Hz), 7.46-7.58 (2H, m)

MS (ESI⁺): m/z 321

Preparation 103

Ethyl 6-(3,5-dichlorobenzoyl)-7-oxooctanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.32-1.42 (2H, m), 1.63-1.75 (2H,m), 1.90-2.12 (2H, m), 2.16 (3H, s), 2.30 (2H, t, J=7 Hz), 4.12 (2H, q,J=7 Hz), 4.32 (1H, t, J=7 Hz), 7.58 (1H, m), 7.82 (2H, m)

Preparation 104

Ethyl 6-[(5-chloro-2-thienyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.30-1.40 (2H, m), 1.62-1.74 (2H,m), 1.90-2.12 (2H, m), 2.16 (3H, s), 2.29 (2H, t, J=7 Hz), 4.13 (2H, q,J=7 Hz), 4.14 (1H, m), 6.98 (1H, d, J=4 Hz), 7.58 (1H, d, J=4 Hz)

Preparation 105

Ethyl 6-(3-fluorobenzoyl)-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.28-1.42 (2H, m), 1.60-1.75 (2H,m), 1.90-2.13 (2H, m), 2.14 (3H, s), 2.29 (2H, t, J=7 Hz), 4.11 (2H, q,J=7 Hz), 4.37 (1H, t, J=7 Hz), 7.26-7.33 (1H, m), 7.43-7.52 (1H, m),7.63-7.68 (1H, m), 7.76 (1H, d, J=8 Hz)

MS (ESI⁺): m/z 309

Preparation 106

Ethyl 7-oxo-6-(3-quinolinylcarbonyl)octanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.35-1.47 (2H, m), 1.63-1.77 (2H,m), 1.98-2.18 (2H, m), 2.20 (3H, s), 2.31 (2H, t, J=7 Hz), 4.10 (2H, q,J=7 Hz), 4.55 (1H, t, J=7 Hz), 7.66 (1H, t, J=8 Hz), 7.87 (1H, t, J=8Hz), 7.97 (1H, d, J=8 Hz), 8.18 (1H, d, J=8 Hz), 8.78 (1H, d, J=2 Hz),9.43 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 342

Preparation 107

Ethyl 6-isonicotinoyl-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.26-1.45 (2H, m), 1.60-1.75 (2H,m), 1.94-2.07 (2H, m), 2.17 (3H, s), 2.27-2.35 (2H, m), 4.11 (2H, q, J=7Hz), 4.38 (1H, t, J=7 Hz), 7.74 (2H, m), 8.83 (2H, m)

Preparation 108

Ethyl 6-[(3-methoxy-5-isoxazolyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.33-1.45 (2H, m), 1.60-1.80 (2H,m), 1.88-2.05 (2H, m), 2.28 (3H, s), 2.30-2.45 (2H, m), 4.03 (3H, s),4.11 (2H, q, J=7 Hz), 4.33 (1H, t, J=7 Hz), 6.56 (1H, s)

MS (ESI⁺): m/z 312

Preparation 109

Ethyl 6-[(5-methyl-3-isoxazolyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.32-1.44 (2H, m), 1.61-1.74 (2H,m), 1.85-2.07 (2H, m), 2.26-2.38 (2H, m), 2.29 (3H, s), 2.49 (3H, s),4.11 (2H, q, J=7 Hz), 4.64 (1H, m), 6.39 (1H, s)

MS (ESI⁺): m/z 296

Preparation 110

Ethyl 6-(2-chloroisonicotinoyl)-8-methoxy-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.28-1.43 (2H, m), 1.66 (2H, t,J=7 Hz), 1.73-1.86 (1H, m), 1.93-2.07 (1H, m), 2.73 (2H, t, J=7 Hz),3.23 (3H, s), 3.89 (1H, d, J=17 Hz), 4.00 (1H, d, J=17 Hz), 4.10 (2H, q,J=7 Hz), 4.58 (1H, t, J=7 Hz), 7.66 (1H, d, J=5 Hz), 7.78 (1H, s), 8.60(1H, d, J=5 Hz)

MS (ESI⁺): m/z 356, MS (ESI⁺): m/z 354

Preparation 111

Ethyl 8-methoxy-6-(3-methoxybenzoyl)-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.60-1.73 (2H,m), 1.79-2.04 (2H, m), 2.28 (2H, t, J=7 Hz), 3.27 (3H, s), 3.87 (3H, s),4.00 (2H, m), 4.12 (2H, q, J=7 Hz), 4.66 (1H, t, J=7 Hz), 7.13 (1H, m),7.39 (1H, m), 7.45-7.55 (2H, m)

Preparation 112

Ethyl 8-methoxy-7-oxo-6-(6-quinolinylcarbonyl)octanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.34-1.47 (2H, m), 1.60-1.75 (2H,m), 1.86-2.10 (2H, m), 2.27 (2H, t, J=7 Hz), 3.24 (3H, s), 4.02-4.10(2H, m), 4.12 (2H, q, J=7 Hz), 4.83 (1H, t, J=7 Hz), 7.48-7.55 (1H, m),8.16-8.33 (3H, m), 8.49 (1H, m), 9.02 (1H, m)

MS (ESI⁺): m/z 372

Preparation 113

Ethyl 8-methoxy-7-oxo-6-(3-pyridinylcarbonyl)octanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.31-1.45 (2H, m), 1.60-1.73 (2H,m), 1.75-2.08 (2H, m), 2.28 (2H, t, J=7 Hz), 3.24 (3H, s), 3.94 (1H, d,J=17 Hz), 4.00 (1H, d, J=17 Hz), 4.10 (2H, q, J=7 Hz), 4.67 (1H, t, J=7Hz), 7.44 (1H, m), 8.22 (1H, m), 8.81 (1H, d, J=5 Hz), 9.18 (1H, m)

MS (ESI⁺): m/z 322

Preparation 114

Ethyl 6-(3-chlorobenzoyl)-8-methoxy-7-oxooctanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.30-1.44 (2H, m), 1.60-1.74 (2H,m), 1.75-1.92 (1H, m), 1.94-2.10 (1H, m), 2.28 (2H, t, J=7 Hz), 3.25(3H, s), 3.93 (1H, d, J=17 Hz), 4.02 (1H, d, J=17 Hz), 4.12 (2H, q, J=7Hz), 4.63 (1H, t, J=7 Hz), 7.43 (1H, t, J=8 Hz), 7.57 (1H, d, J=8 Hz),7.83 (1H, d, J=8 Hz), 7.94 (1H, s)

Preparation 115

Ethyl 6-(3-methylbenzoyl)-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.29-1.42 (2H, m), 1.60-1.73 (2H,m), 1.90-2.06 (2H, m), 2.13 (3H, s), 2.28 (2H, t, J=7 Hz), 2.42 (3H, s),4.10 (2H, q, J=7 Hz), 4.42 (1H, t, J=7 Hz), 7.31-7.43 (2H, m), 7.73-7.78(2H, m)

Preparation 118

Ethyl 8-methoxy-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.30-1.47 (2H, m), 1.60-1.74 (2H,m), 1.75-1.93 (1H, m), 1.93-2.08 (1H, m), 2.26 (2H, t, J=7 Hz), 2.43(3H, s), 3.25 (3H, s), 3.95 (1H, d, J=17 Hz), 4.03 (1H, d, J=17 Hz),4.12 (2H, q, J=7 Hz), 4.67 (1H, t, J=7 Hz), 8.03 (1H, s), 8.63 (1H, s),8.98 (1H, s)

MS (ESI⁺): m/z 336

Preparation 119

Ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.32-1.43 (2H, m), 1.60-1.76 (2H,m), 1.96-2.15 (2H, m), 2.19 (3H, s), 2.30 (2H, t, J=7 Hz), 4.12 (2H, q,J=7 Hz), 4.36 (1H, t, J=7 Hz), 8.37 (1H, s), 8.87 (1H, br), 9.07 (1H,br)

MS (ESI⁺): m/z 370, 372

Preparation 120

Ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-8-methoxy-7-oxooctanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.30-1.47 (2H, m), 1.60-1.72 (2H,m), 1.75-1.93 (1H, m), 1.95-2.08 (1H, m), 2.27 (2H, t, J=7 Hz), 3.25(3H, s), 3.93 (1H, d, J=17 Hz), 4.02 (1H, d, J=17 Hz), 4.10 (2H, q, J=7Hz), 4.63 (1H, t, J=7 Hz), 8.38 (1H, m), 8.88 (1H, m), 9.07 (1H, m)

MS (ESI⁺): m/z 400, 402

Preparation 121

Ethyl 6-[(5,6-dichloro-3-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.60-1.77 (2H,m), 1.95-2.17 (2H, m), 2.19 (3H, s), 2.30 (2H, t, J=7 Hz), 4.11 (2H, q,J=7 Hz), 4.32 (1H, t, J=7 Hz), 8.31 (1H, d, J=2 Hz), 8.82 (1H, d, J=2Hz)

Preparation 122

Ethyl 7-methoxy-5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxoheptanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.60-1.75 (2H, m), 1.78-1.95 (1H,m), 1.95-2.12 (1H, m), 2.32 (2H, t, J=7 Hz), 2.44 (3H, s), 3.25 (3H, s),3.94 (1H, d, J=18 Hz), 4.02 (1H, d, J=18 Hz), 4.12 (2H, q, J=7 Hz), 4.69(1H, t, J=7 Hz), 8.04 (1H, s), 8.63 (1H, s), 9.00 (1H, s)

MS (ESI⁺): m/z 322

Preparation 123

Ethyl 6-methoxy-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 2.08-2.55 (4H, m), 2.44 (3H, s),3.23 (3H, s), 3.94 (1H, d, J=18 Hz), 4.01 (1H, d, J=18 Hz), 4.12 (2H, q,J=7 Hz), 4.88 (1H, m), 8.12 (1H, s), 8.64 (1H, s), 9.04 (1H, s)

MS (ESI⁺): m/z 308

Preparation 124

Ethyl 5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxoheptanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.60-1.75 (2H, m), 1.96-2.13 (2H,m), 2.18 (3H, s), 2.36 (2H, t, J=7 Hz), 2.43 (3H, s), 4.12 (2H, q, J=7Hz), 4.43 (1H, t, J=7 Hz), 8.04 (1H, s), 8.63 (1H, s), 8.97 (1H, s)

MS (ESI⁺): m/z 292

Preparation 125

Ethyl 4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 2.20 (3H, s), 2.26-2.48 (4H, m),2.43 (3H, s), 4.13 (2H, q, J=7 Hz), 4.62 (1H, t, J=7 Hz), 8.08 (1H, s),8.64 (1H, s), 9.02 (1H, s)

MS (ESI⁺): m/z 278

Preparation 126

Ethyl 4-[(5-bromo-3-pyridinyl)carbonyl]-5-oxohexanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 2.26 (3H, s), 2.30 (2H, t, J=7Hz), 2.43 (2H, t, J=7 Hz), 4.15 (2H, q, J=7 Hz), 8.65(1H, s), 8.94 (1H,s), 9.22(1H, s)

Preparation 127

Ethyl 6-(3-cyanobenzoyl)-8-methoxy-7-oxooctanoate

NMR (CDCl₃, δ): 1.19-1.43 (12H, m), 1.57-1.70 (2H, m), 1.80 (1H, m),1.99 (1H, m), 2.28 (2H, t, J=8 Hz), 3.24 (3H, s), 3.91 (1H, d, J=16 Hz),4.01 (1H, d, J=16 Hz), 4.09 (2H, q, J=8 Hz), 4.65 (1H, t, J=8 Hz), 7.64(1H, t, J=8 Hz), 7.87 (1H, dd, J=8, 1 Hz), 8.18 (1H, dd, J=8, 1 Hz),8.25 (1H, br s)

Preparation 128

Ethyl 8-(acetyloxy)-6-[(5-bromo-3-pyridinyl)carbonyl]-7-oxooctanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.37 (2H, m), 1.67 (2H, m),1.98-2.06 (5H, m), 2.30 (2H, t, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.47 (1H,t, J=7 Hz), 4.66 (d, J=17 Hz), 4.74 (d, J=17 Hz), 8.37 (1H, m), 8.88(1H, m), 9.06 (1H, m)

Preparation 129

To a solution of Meldrum's acid (30 g, 0.208 mol) in dichloromethane(420 mL) was added pyridine (33.7 mL, 0.416 mol) over 3 minutes in anice-methanol bath under nitrogen atmosphere (−9° C.). To this mixturewas added dropwise a solution of methoxyacetyl chloride (24.8 g) indichloromethane (180 mL) over 1 hour period at the temperature. Afteraddition, the reaction mixture was stirred at the temperature for 1 hourand at ambient temperature for 2 hours. The mixture was quenched with 1Nhydrochoric acid (600 mL). The organic layer was separated and theaqueous layer was extracted with dichloromethane. The combined organiclayer was washed with brine, dried over magnesium sulfate, andevaporated in vacuo to give5-(methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione as dark orange oil(38.1 g, 84.7%).

5-(Methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione

NMR (CDCl₃, δ): 1.75 (6H, s), 3.53 (3H, s), 4.87 (2H, s)

Preparation 130

A solution of 5-(methoxyacetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (38g) in tert-butanol (120 mL) and toluene (120 mL) was refluxed for 2hours under nitrogen atmosphere. The mixture was evaporated in vacuo togive brown oil (325 g). The residue was dissolved in hexane-ethylacetate=2-1 (200 mL) and was added silica gel (65 g) therein. Afterstirring for 30 minutes at ambient temperature, the mixture was filteredand washed with hexane-ethyl acetate=2-1 (200 mL). The filtrate wasconcentrated in vacuo to give tert-butyl 4-methoxy-3-oxobutanoate aspale yellow oil (30.1 g, 91.0%).

tert-Butyl 4-methoxy-3-oxobutanoate

NMR (CDCl₃, δ): 150 (9H, s), 3.41 (2H, s), 3.43 (3H, s), 4.08 (2H, s)

Preparation 131

To a mixture of 3-formylbenzoic acid (500 mg) andp-toluenesulfonylmethyl isocyanide (715 mg) in methanol (20 mL) wasadded potassium carbonate (1.38 g) and the mixture was heated underreflux for 2 hours. After evaporation of solvent, the residue waspartitioned between ethyl acetate and water. The aqueous layer wasseparated and acidified with 1N hydrochloric acid. The resultingprecipitates were collected and washed with water, methanol and ether togive 3-(1,3-oxazol-5-yl)benzoic acid as a colorless amorphous powder(484 mg).

3-(1,3-Oxazol-5-yl)benzoic acid

NMR (DMSO-d₆, δ): 7.63 (1H, t, J=8 Hz), 7.84 (1H, s), 7.89-8.02 (2H, m),8.25 (1H, m), 8.50 (1H, s), 13.22 (1H, br)

MS (ESI⁺): m/z 188 (M−H)

Preparation 132

A mixture of 1-(3-chlorophenyl)-1,3-butanedione (500 mg),5-(iodomethyl)-2,2-dimethyl-1,3-dioxane (716 mg), and potassiumcarbonate (351 mg) in dimethylsulfoxide (2.5 mL) was stirred for 14hours at room temperature and 7 hours at 40° C. The mixture waspartitioned between ethyl acetate (20 mL) and water (10 mL). The organiclayer was washed with water (10×2 mL) and brine, dried over magnesiumsulfate, and evaporated to give a brown oil. Flash silica gel columnchromatography eluting with ethyl acetate-hexane=1-10 to 2-5 afforded1-(3-chlorophenyl)-2-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-1,3-butanedioneas an yellow oil (614 mg).

1-(3-Chlorophenyl)-2-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-1,3-butanedione

NMR (CDCl₃, δ): 1.39 (6H, s), 1.70 (1H, m), 1.91-2.15 (2H, m), 2.16 (3H,s), 3.61 (2H, m), 3.88 (2H, m), 4.46 (1H, t, J=7 Hz), 7.44 (1H, t, J=9Hz), 7.57 (1H, m), 7.86 (1H, d, J=9 Hz), 7.96 (1H, m)

The following compounds were obtained in substantially the same manneras that of Preparation 132.

Preparation 133

1-tert-Butyl 7-ethyl 2-(1,3-oxazol-5-ylcarbonyl)heptanedioate

NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.32-1.38 (11H, m), 1.67 (2H, m),1.97 (2H, m), 2.30 (2H, m), 3.86 (1H, t, 3=7 Hz), 4.11 (2H, q, J=7 Hz),7.86 (1H, s), 8.03 (1H, s)

Preparation 134

1-tert-Butyl 7-ethyl2-[(3,5-dimethyl-4-isoxazolyl)carbonyl]heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.33-1.41 (11H, m), 1.64 (2H, m),1.93 (2H, m), 2.30 (2H, m), 2.47 (3H, s), 2.69 (2H, s), 3.79 (1H, t, J=7Hz), 4.12 (2H, q, J=7 Hz)

Preparation 135

To a suspensin of magnesium chloride (1.46 g) in tetrahydrofuran (10 ml)was added a solution of ethyl 3-oxo-4-phenylbutanoate (2.0 g) intetrahydrofuran (10 ml) and the mixture was cooled to 0° C., thenpyridine (25 ml) was added. The mixture was stirred at 20° C. for 30minutes, then a solution of 4-fluorobenzoyl chloride (2.44 g) intetrahydrofuran (10 ml) was added at 0° C. After stirring at 20° C. for2 hours, the mixure was partitoned between 0.5N hydrochloric acid andethyl acetate. The organic layer was separated, washed with water andbrine, dried over magnesium sulfate, and evaporated. The residue waschromatographed on silica gel eluting with a mixture of ethyl acetateand hexane (1:5) to give ethyl2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (2.15 g) as an oil.

Ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate

(mixture of tautomers, too complicated to be assigned)

Preparation 136

A mixture of 1-(4-fluorophenyl)butane-1,3-dione (1.0 g), potassiumcarbonate (3.42 g), and tetrabutylammonium bromide (20 mg) in toluene(10 ml) was refluxed for 3 hours. After cooling to 20° C., ethylbromoacetate (0.74 ml) was added to the mixture. After being allowed tostand at 20° C. overnight, the mixture was partitoned between ethylacetate and 0.5N hydrochloric acid. The organic layer was separated,washed with water and brine, dried over magnesium sulfate, andevaporated. The residue was chromatographed on silica gel eluting with amixture of ethyl acetate and hexane (1:5) to give ethyl3-(4-fluorobenzoyl)-4-oxopentanoate (964 mg) as an oil.

Ethyl 3-(4-fluorobenzoyl)-4-oxopentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 2.18 (3H, s), 3.01 (2H, d, J=7Hz), 4.12 (2H, q, J=7 Hz), 4.95 (1H, d, J=7 Hz), 7.18 (2H, dt, J=2, 7Hz), 8.07 (2H, ddd, J=2, 5, 7 Hz)

Preparation 137

A mixture of 1-(4-fluorophenyl)butane-1,3-dione (1.0 g), potassiumcarbonate (3.84 g), and tetrabutylammonium bromide (90 mg) in toluene(20 ml) was refluxed for 3 hours, then ethyl 6-bromohexanoate (1.18 ml)was added. After stirring at 100° C. for 3 hours, the mixture waspartitoned between ethyl acetate and 0.5N hydrochloric acid. The organiclayer was separated, washed with water and brine, dried over magnesiumsulfate, and evaporated. The residue was chromatographed on silica geleluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl7-(4-fluorobenzoyl)-8-oxononanoate (983 mg) as an oil.

Ethyl 7-(4-fluorobenzoyl)-8-oxononanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.25-1.45 (4H, m), 1.55-1.70 (2H,m), 1.90-2.10 (2H, m), 2.13 (3H, s), 2.27 (2H, t, J=7 Hz), 4.11 (2H, q,J=7 Hz), 4.37 (1H, t, J=7 Hz), 7.16 (2H, t, J=9 Hz), 8.02 (2H, dd, J=5,9 Hz)

Preparation 138

A mixture of pentane-2,4-dione (5.0 g), ethyl 7-bromoheptanoate (11.1g), potassium carbonate (13.8 g), and cesium carbonate (1.63 g) in amixture of acetonitrile (150 ml) and dimethylsulfoxide (30 ml) wasstirred at 20° C. overnight, then pentane-2,4-dione (5 g) was added.After stirring at 20° C. overnight, the mixture was partitoned betweenethyl acetate and 0.5N hydrochloric acid. The organic layer wasseparated, washed with water and brine, dried over magnesium sulfate,and evaporated. The residue was chromatographed on silica gel elutingwith a mixture of ethyl acetate and hexane (1:5) to give ethyl8-acetyl-9-oxodecanoate (55 g) as an oil.

Ethyl 7-acetyl-8-oxononanoate

(mixture of tautomers, too complicated to be assigned)

Preparation 139

To a mixture of ethyl 7-acetyl-8-oxononanoate (4.0 g) and magnesiumchloride (1.27 g) in dichloromethane (70 ml) was added pyridine (2.15ml) at 0° C. The mixture was stirred at 20° C. for 1 hour, then asolution of 4-cyanobenzoyl chloride (2.87 g) in dichloromethane (10 ml)was added. After stirring for 3 hours at 20° C., the mixture waspartitioned between ether and 1N hydrochloric acid. The organic layerwas separated, washed with water and brine, dried over magnesiumsulfate, and evaporated. The residue was chromatographed on silica geleluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl7-acetyl-7-(4-cyanobenzoyl)-8-oxononanoate (352 g) as an oil.

1-tert-Butyl 8-ethyl 2-acetyl-2-(4-cyanobenzoyl)octanedioate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.25-1.45 (4H, m), 1.30 (9H, s),1.55-1.70 (2H, m), 2.20 (2H, t, J=7 Hz), 2.28 (2H, t, J=7 Hz), 2.44 (3H,s), 4.12 (2H, q, J=7 Hz), 7.72 (2H, t, J=9 Hz), 7.83 (2H, d, J=9 Hz)

Preparation 140

Ethyl 7-acetyl-7-(4-cyanobenzoyl)-8-oxononanoate (3.5 g) was dissolvedin trifluoroacetic acid (12.6 ml) and the mixture was stirred at 20° C.for 15 minutes. The mixture was partitoned between ethyl acetate andwater. The organic layer was separated, washed with water, aqueoussodium bicarbonate and brine, dried over MgSO₄ (magnesium sulfate), andevaporated to give ethyl 7-(4-cyanobenzoyl)-8-oxononanoate (2.25 g) asan oil.

Ethyl 7-(4-cyanobenzoyl)-8-oxononanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.25-1.45 (4H, m), 1.55-1.70 (2H,m), 1.80-2.10 (2H, m), 2.16 (3H, s), 2.28 (2H, t, J=7 Hz), 4.12 (2H, q,J=7 Hz), 4.40 (1H, t, J=7 Hz), 7.80 (2H, t, J=9 Hz), 8.07 (2H, d, J=9Hz)

Preparation 141

A mixture of methyl 4-(aminosulfonyl)benzoate (5.10 g) and potassiumcarbonate (655 g) in dimethoxyethane (50 mL) was refluxed for 5 minutes.After cooling the mixture, a solution of benzyl chloridocarbonate (5.25g) in dimethoxyethane (30 mL), and the resulting mixture was refluxedfor 1 hour. The reaction was quenched by adding 1N hydrochloric acid(100 mL). The mixture was extracted with ethyl acetate (200 mL), and theorganic layer was washed with brine, dried over magnesium sulfate, andevaporated to give a pale yellow oil, which was solidified uponstanding. The solid was triturated in diisopropyl ether (30 mL) to givemethyl 4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate as a whitepowder (3.38 g).

Methyl 4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate

NMR (CDCl₃, δ): 3.98 (3H, s), 5.10 (2H, s), 7.22 (2H, m), 7.34 (3H, m),7.64 (1H, s, br), 8.08 (2H, d, J=9 Hz), 8.16 (2H, d, J=9 Hz)

Preparation 142

A suspension of methyl 4-({[(benzyloxy)carbonyl]amino}sulfonyl)benzoate(3.38 g) and 85% pottasium hydroxide (1.28 g) in methanol (40 mL) wasstirred for 35 minutes. Methanol was evaporated off, and to the mixturewas added 1N hydrochloric acid (20 mL). A white crystal was formed,which was collected by filtration and washed with water and diisopropylether, and dried under vacuum.4-({[(Benzyloxy)carbonyl]amino}sulfonyl)benzoic acid was obtained as awhite crystal (2.92 g).

4-({[(Benzyloxy)carbonyl]amino}sulfonyl)benzoic acid

NMR (DMSO-d₆, δ): 5.06 (2H, s), 7.25 (2H, m), 7.33 (3H, m), 8.00 (2H, d,J=9 Hz), 8.15 (2H, d, J=9 Hz)

MS (ESI⁻): m/z 334 (M−H)

Preparation 143

To a suspension of S-(2-pyridinyl) 3-cyanobenzenecarbothioate (2.40 g)in toluene (10 mL) was added titanium chloride (1.99 g) under anice-methanol bath over 5 minutes (−7 to −2° C.). After stirring for 10minutes, a solution of 2-ethyl-1H-pyrrole (1.00 g) in toluene (10 mL)was added over 5 minutes (−4 to 0° C.). The resulting heterogeneousmixture was stirred for 15 hours at room temperature. Ethyl acetate (20mL) and water (20 mL) were added, and the mixture was filtered throughcelite. The filtrate was diluted with ethyl acetate (80 mL) and water(30 mL), and organic extract was washed with water (30 mL), 1N sodiumhydroxide (50 mL), and brine (50 mL), dried over magnesium sulfate, andevaporated to give a dark colored crystal (2.46 g). The crystal wastriturated in diisopropyl ether (10 mL) to give3-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile as a brown crystal (157g, 70.1%).

3-[(5-Ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile

NMR (CDCl₃, δ): 1.33 (3H, t, J=7 Hz), 2.75 (2H, q, J=7 Hz), 6.12 (1H,m), 6.78 (1H, m), 7.60 (1H, t, J=8 Hz), 7.82 (1H, d, J=8 Hz), 8.07 (1H,d, J=8 Hz), 8.14 (1H, s), 9.50 (1H, s, br)

Preparation 144

To a suspension of magnesium chloride (3.01 g) in tetrahydrofuran (30mL) was added tert-butyl 3-oxobutanoate (5.00 g). The mixture was cooledunder an ice-bath. Then, pyridine (5.00 g) was added over 15 minutes.After stirring for 1 hour at room temperature, the resulting mixture wascooled under the ice-bath. A solution of 2-chlorobenzoyl chloride (4.98g) in tetrahydrofuran (30 mL) was added over 15 minutes. The mixture wasstirred for 1 hour at room temperature. The reaction was quenched byadding 1N hydrochloric acid (65 mL). The mixture was filtered, and thesolvent was evaporated off. The residue was extracted with ethyl acetate(150 mL). The extract was washed with water (100 mL), saturated sodiumbicarbonate (100 mL), and brine, dried over magnesium sulfate, andevaporated to give tert-butyl 2-(3-chlorobenzoyl)-3-oxobutanoate as anyellow oil (8.82 g).

tert-Butyl 2-(3-chlorobenzoyl)-3-oxobutanoate

NMR (CDCl₃, δ): mixture of tautomers: 1.20 and 1.27 (9H, s), 2.16 and2.44 (3H, s), 7.33-7.71 (4H, m), 13.66 (1H, s)

Preparation 145

A solution of tert-butyl 2-(3-chlorobenzoyl)-3-oxobutanoate (8.82 g) intrifluoroacetic acid (40 mL) was stirred for 1 hour under an ice-bath.The volatile was removed in vacuo, and the residue was partitionedbetween ethyl acetate (150 mL) and saturated sodium bicarbonate. Theorganic layer was washed with brine, dried over magnesium sulfate, andevaporated to give 1-(3-chlorophenyl)-1,3-butanedione as a pale orangecrystal (533 g).

1-(3-Chlorophenyl)-1,3-butanedione

NMR (CDCl₃, δ): 2.21 (3H, s), 6.14 (1H, s), 7.38 (1H, t, J=9 Hz), 7.48(1H, d, J=9 Hz), 7.75 (1H, d, J=9 Hz), 7.85 (1H, s)

Preparation 146

To a mixture of 2-(trimethylsilyl)ethanol (20.5 g) and pyridine (18.7 g)in dichloromethane (40 mL) was added a solution of ethanedioyldichloride (10.0 g) in dichloromethane (20 mL) over 30 minutes under anice-bath (6 to 20° C.). The bath was removed, and the mixture wasstirred for 0.5 hour. The mixture was filtered, and the filtrate waspartitioned between ethyl acetate (200 mL) and 1N hydrochloric acid (200mL). The organic layer was washed with saturated sodium bicarbonate andbrine, dried over magnesium sulfate, and evaporated to givebis[2-(trimethylsilyl)ethyl]oxalate as a pale yellow oil (25.1 g).

bis[2-(Trimethylsilyl)ethyl]oxalate

NMR (CDCl₃, δ): 0.08 (18H, s), 1.12 (4H, m), 4.38 (4H, m)

Preparation 147

To a suspension of dimethyl sulfone (7.00 g) in diethyl ether (50 mL)was added potassium tert-butoxide (8.76 g). To the resulting mixture wasadded bis[2-(trimethylsilyl)ethyl]oxalate (23.8 g). The resultingmixture was stirred for 36 hours at room temperature. The mixture waspartitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (50mL). The organic layer was washed with brine, dried over magnesiumsufate, and evaporated to give a dark orange oil. Flash silica gelcolumn chromatography eluting with ethyl acetate-hexane=1-25 to 8-5afforded 2-(trimethylsilyl)ethyl 3-(methylsulfonyl)-2-oxopropanoate as apale brown oil (8.37 g).

2-(Trimethylsilyl)ethyl 3-(methylsulfonyl)-2-oxopropanoate

NMR (CDCl₃, δ): 0.08 (9H, s), 1.14 (2H, m), 3.11 (3H, s), 4.43 (4H, m),4.56 (2H, s)

MS (ESI⁻): m/z 265 (M−H)

Preparation 148

A mixture of 4-oxo-4-phenylbutanoic acid (5.00 g), ethanol (2.59 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.46 g),and 4-(dimethylamino)pyridine (171 mg) in N,N-dimethylformamide (25 mL)was stirred for 1.5 hours at room temperature. The mixture waspartitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (75mL), and the organic layer was washed with water (75×3 mL), saturatedsodium bicarbonate (75 mL), and brine (75 mL), dried over magnesiumsulfate, and evaporated to give ethyl 4-oxo-4-phenylbutanoate as acolorless oil (4.19 g).

Ethyl 4-oxo-4-phenylbutanoate

NMR (CDCl₃, δ): 1.27 (3H, t, J=7 Hz), 2.76 (2H, t, J=7 Hz), 3.32 (2H, t,J=7 Hz), 4.16 (2H, q, J=7 Hz), 7.47 (2H, t, J=9 Hz), 7.55 (1H, d, J=9Hz), 7.98 (2H, d, J=9 Hz)

MS (ESI⁺): m/Z 207 (M+H)

The following compound was obtained in substantially the same manner asthat of Preparation 148.

Preparation 149

Ethyl 5-oxo-5-phenylpentanoate

NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 2.08 (2H, m), 2.44 (2H, t, J=7Hz), 3.06 (2H, t, J=7 Hz), 4.14 (2H, q, J=7 Hz), 7.46 (2H, t, J=9 Hz),7.56 (1H, d, J=9 Hz), 7.97 (2H, d, J=9 Hz)

MS (ESI⁺): m/z 221 (M+H)

Preparation 150

A mixture of 2-benzoylcyclohexanone (1.00 g), sodium ethoxide (404 mg)in ethanol (5 mL) was stirred for 3.5 hours at room temperature. Thereaction was quenched by adding 1N hydrochloric acid (1 mL). The solventwas evaporated off, and the residue was partitioned between ethylacetate and water. The organic layer was washed with brine, dried overmagnesium sulfate, and evaporated to give ethyl 7-oxo-7-phenylheptanoateas a brown oil (1.33 g).

Ethyl 7-oxo-7-phenylheptanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.42 (2H, m), 1.63-1.81 (4H, m),2.32 (2H, t, J=7 Hz), 2.98 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 7.47(2H, t, J=9 Hz), 7.54 (1H, d, J=7 Hz), 7.95 (2H, d, J=9 Hz)

Preparation 151

To a solution of ethyl 7-chloro-7-oxoheptanoate (1.31 g) indichloromethane (25 mL) was added a solution of2-(trimethylsilyl)-1,3-thiazole (500 mg) in dichloromethane (5 mL) undernitrogen. After stirring for 3 hours, the reaction was quenched byadding saturated sodium bicarbonate (5 mL). The mixture was partitionedbetween ethyl acetate (30 mL) and saturated sodium bicarbonate (30 mL),and the organic layer was washed with brine, dried over magnesiumsulfate, and evaporated to give a colorless oil. Flash silica gel columnchromatography eluting with ethyl acetate-hexane=1-10 to 2-5 affordedethyl 7-oxo-7-(1,3-thiazol-2-yl)heptanoate as a colorless oil (778 mg).

Ethyl 7-oxo-7-(1,3-thiazol-2-yl)heptanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.44 (2H, m), 1.64-1.85 (4H, m),2.32 (2H, t, J=7 Hz), 3.17 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 7.66(1H, d, J=3 Hz), 8.00 (1H, d, J=3 Hz)

MS (ESI⁺): m/z 256 (M+H)

Preparation 152

To a solution of 7-methoxy-7-oxoheptanoic acid (1.00 g) indichloromethane (10 mL) was added a solution of trifluoroaceticanhydride (1.33 g) in dichloromethane (2 mL). After stirring for 0.5hour, a solution of 1-methyl-1H-pyrrole (1.49 g) in dichloromethane (2mL) was added. The mixture was stirred for 2 hours 40 minutes at roomtemperature and 2 hours at 35° C. The mixture was partitioned betweenethyl acetate and saturated sodium bicarbonate. The organic layer waswashed with brine, dried over magnesium sulfate, and evaporated to givea brmown oil. Flash silica gel column chromatography eluting with ethylacetate-hexane=1-20 to 4-5 afforded methyl7-(1-methyl-1H-pyrrol-2-yl)-7-oxoheptanoate as a colorless oil (615 mg).Methyl 7-(1-methyl-1H-pyrrol-2-yl)-7-oxoheptanoate

NMR (CDCl₃, δ): 1.34 (2H, m), 1.61-1.77 (4H, m), 2.32 (2H, t, J=7 Hz),2.77 (2H, t, J=7 Hz), 3.66 (3H, s), 3.94 (3H, s), 6.13 (1H, m), 6.79(1H, m), 6.93 (1H, m)

MS (ESI⁺): m/z 238 (M+H)

Preparation 153

To a suspension of 4-({[(benzyloxy)carbonyl]amino}-sulfonyl)benzoic acid(2.90 g) in dichloromethane (30 mL) was added N,N-dimethylformamide(19.0 mg) and followed by oxalyl chloride (1.15 g) under an ice-bath.The mixture was stirred for 0.5 hour at room temperature and refluxedfor 1 hour. The resulting mixture was refluxed further for 5 minutesafter adding oxalyl chloride (439 mg). The volatile was evaporated offto give a white solid. The solid was triturated in diisopropyl ether togive benzyl [4-(chlorocarbonyl)phenyl]sulfonylcarbamate as a whitepowder (2.40 g), which was used for the next reaction without furtherpurification.

Benzyl [4-(chlorocarbonyl)phenyl]sulfonylcarbamate

Preparation 154

To a solution of tert-butyl 4-(methylthio)-3-oxobutanoate (5.00 g) andpotassium carbonate (3.72 g) in dimethylformamide (25 mL) was addedethyl 5-iodopentanoate (6.89 g) and the mixture was stirred at ambienttemperature for 15 hours. The mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with waterand brine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by silica gel column chromatography eluting with amixture of hexane and ethyl acetate (20:1-10:1) to give 1-tert-butyl7-ethyl 2-[(methylthio)acetyl]heptanedioate as colorless oil (5.88 g).

1-tert-butyl 7-ethyl 2-[(methylthio)acetyl]heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.30-1.42 (2H, m), 1.45 (9H, s),1.63-1.74 (2H, m), 1.81-1.93 (2H, m), 2.05 (3H, s), 2.30 (2H, t, J=7Hz), 3.23 (1H, d, J=17 Hz), 3.38 (1H, d, J=17 Hz), 3.74 (1H, t, J=7 Hz),4.11 (2H, q, J=7 Hz)

Preparation 155

To a suspension of hydroxylamine hydrochloride (29.4 g) indichloromethane (200 mL) was added diisopropylethylamine (54.6 g) over 3minutes in a methanol-ice bath under a nitrogen atmosphere. A whiteprecipitate was formed upon the addition. After stirring for 1 hourunder the bath, a solution of diphenylphosphinic chloride (20.0 g) indichloromethane (20 mL) was added over 60 minutes. A white crystal wasformed upon the addition. The mixture was warmed to 0° C. over 1 hourwith stirring. The reaction was quenched by adding water (200 mL) over 3minutes. After stirring the mixture for 0.5 hour, the crystal wascollected by filtration. The crystal was washed with water (50×3 mL)followed by diisopropyl ether (50×3 mL). The collected crystal was driedovernight in the air and 3 hours under a reduced pressure with slightwarming (4° C.) to give a crude product. The crude product wastriturated in EtOH (ethanol) to give (aminooxy)(diphenyl)phosphine oxideas a white crystal (15.3 g).

(Aminooxy)(diphenyl)phosphine oxide

NMR (CDCl₃, δ): 7.54-7.58 (6H, m), 7.74-7.83 (4H, m), 8.20-8.33 (2H, m)

Preparation 156

To a solution of 1-(1H-pyrrol-2-yl)ethanone (5.00 g) in tetrahydrofuran(100 mL) was added potassium tert-butoxide (6.17 g) in a water bathunder a nitrogen atmosphere. After stirring for 1 hour,(aminooxy)(diphenyl)phosphine oxide (12.8 g) was added over 2 hours.After stirring for 2 hours at room temperature, water (4 mL) was addedover 3 minutes to give a clear solution. The solvent was evaporated off,and the residue was partitioned between ethyl acetate (50 mL) and water(50 mL). The aqueous layer was extracted with ethyl acetate (25×5 mL),and the combined organic extract was washed with brine, dried overanhydrous magnesium sulfate, and evaporated to give a brown oil (6.01g). The oil was dissolved in diisopropyl ether (30 mL), and to thesolution was added hexane (15 mL) to afford a pale yellow crystal. Afterstirring for 1 hour, the crystal was removed by filtration. The filtratewas evaporated to give a brown oil (5.69 g). The oil was dissolved inethyl acetate (45.5 mL), the solution was cooled under an ice-bath. Tothe cooled solution was added 4N hydrogen chloride in ethyl acetate (115mL) over 15 minutes to afford a pale brown precipitate. After stirringthe mixture for 0.5 hour under the bath, the precipitate was collectedby filtration and washed with ethyl acetate (5×3 mL) to give a palebrown powder (5.33 g). The powder was suspended in ethyl acetate (37 mL)and warmed to 3° C. The suspension was stirred for 1 hour at roomtemperature. The powder was collected by filtration and washed withethyl acetate (5×3 mL) to give 1-(1-amino-1H-pyrrol-2-yl)ethanonehydrochloride as a pale brown powder (5.25 g).

1-(1-Amino-1H-pyrrol-2-yl)ethanone hydrochloride

NMR (CDCl₃, δ): 2.37 (3H, s), 5.22 (2H, s, br), 6.07 (1H, m), 6.99 (1H,m), 7.15 (1H, m)

Preparation 157

Under a nitrogen atmosphere, hydrazine monohydrate (530 g) was added toethanol (1.7 L) over 55 minutes. To the mixture was added1-(1-amino-1H-pyrrol-2-yl)ethanone hydrochloride (170 g) over 20minutes. The mixture was stirred for 10 minutes at room temperature andheated to refluxing temperature over 55 minutes, and refluxed for 15minutes. After cooling the mixture under a water bath, water (1.7 L) wasadded to the mixture (30 to 31° C.). Ethanol was evaporated off, and theresulting mixture was extracted with chloroform (0.85×4 mL). Thecombined organic extract was washed with brine (1.3 L). The brine wasextracted with chloroform (0.85 L). The combined organic extract wasdried over anhydrous magnesium sulfate, and evaporated to give(1E)-1-(1-amino-1H-pyrrol-2-yl)ethanone hydrazone as a brown crystal(112 g).

(1E)-1-(1-Amino-1H-pyrrol-2-yl)ethanone hydrazone

NMR (CDCl₃, δ): 2.10 (3H, s), 5.11 (2H, s, br), 5.83 (2H, s, br), 5.98(1H, m), 6.25 (1H, m), 6.79 (1H, m)

MS (ESI⁺): m/z 139 (M+H)

Preparation 158

To a suspension of (1E)-1-(1-amino-1H-pyrrol-2-yl)ethanone hydrazone(110 g) in toluene (1.1 L) was added potassium tert-butoxide (93.8 g)over 5 minutes under a nitrogen atmosphere, and the mixture was heatedto refluxing temperature over 45 minutes. After refluxing for 15minutes, the mixture was cooled to room temperature and partitionedbetween ethyl acetate (1.1 L) and water (1.1 L). The aqueous layer wasextracted with ethyl acetate (1.1 L) again. The combined organic extractwas was washed with brine (1.1 L), and the brine was extracted withethyl acetate (0.5 L). All the organic layer was combined, dried overanhydrous magnesium sulfate, and evaporated to give2-ethyl-1H-pyrrol-1-amine as a brown oil (94.4 g).

2-Ethyl-1H-pyrrol-1-amine

NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 21.62 (2H, q, J=7 Hz), 4.53 (2H,s, br), 5.80 (1H, m), 5.99 (1H, m), 6.67 (1H, m)

Preparation 159

To a suspension of tert-butyl 4-methoxy-3-oxobutanoate (3.09 g) andpotassium carbonate (2.50 g) in dimethylformamide (20 mL) was addedethyl 5-iodopentanoate (4.62 g) and the mixture was stirred at ambienttemperature for 15 hours. The mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with waterand brine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by silica gel column chromatography eluting with amixture of hexane and ethyl acetate (20:1-5:1) to give 1-tert-butyl7-ethyl 2-(methoxyacetyl)heptanedioate as colorless oil (4.33 g).

1-tert-Butyl 7-ethyl 2-(methoxyacetyl)heptanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.30-1.44 (2H, m), 1.45 (9H, s),1.60-1.73 (2H, m), 1.80-1.93 (2H, m), 2.29 (2H, t, J=7 Hz), 3.41 (3H,s), 3.47 (1H, t, J=7 Hz), δ 4.02 (4H, m)

MS: (m/z) 317 (M+H)

The following compounds were obtained in substantially the same manneras that of Preparation 159.

Preparation 160

1-tert-Butyl 6-ethyl 2-(methoxyacetyl)hexanedioate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.46 (9H, s), 1.52-1.73 (2H, m),1.82-1.94 (2H, m), 2.33 (2H, t, J=7 Hz), 3.42 (3H, s), 3.50 (1H, t, J=7Hz), 4.10 (2H, s), 4.12 (2H, q, J=7 Hz)

Preparation 161

1-tert-Butyl 5-ethyl 2-(methoxyacetyl)pentanedioate

NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.47 (9H, s), 2.10-2.25 (2H, m),2.37 (2H, t, J=7 Hz), 3.42 (3H, s), 3.62 (1H, t, J=7 Hz), 4.12 (2H, s),4.13 (2H, q, J=7 Hz)

Preparation 162

1-tert-Butyl 6-ethyl 2-acetylhexanedioate

NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.47 (9H, s), 1.57-1.75 (2H, m),1.79-1.93 (2H, m), 2.23 (3H, s), 2.33 (2H, t, J=7 Hz), 3.33 (1H, t, J=7Hz), 4.12 (2H, q, J=7 Hz)

MS (ESI⁺): m/z 273

Preparation 163

1-tert-Butyl 5-ethyl 2-acetylpentanedioate

NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.47 (9H, s), 2.08-2.22 (2H, m),2.24 (3H, s), 2.33-2.42 (2H, m), 3.45 (1H, t, J=7 Hz), 4.13 (2H, q, J=7Hz)

Preparation 164

To a solution of 2-ethyl-1H-pyrrole (7.00 g) in tetrahydrofuran (14 mL)was added 0.93 M ethyl magnesium bromide (198 mL) under an ice-bath. Themixture was stirred for 1 hour at room temperature. Then the resultingsolution was added to a suspension of 5-bromonicotinoyl chloride (22.3g) in tetrahydrofuran (110 mL) over 50 minutes under an ice-bath. Afterstirring for 15 minutes under the bath, the reaction was quenched byadding saturated ammonium chloride (30 mL). The mixture was partitionedbetween ethyl acetate (350 mL) and water (350 mL). The organic layer waswashed with saturated sodium bicarbonate and brine, dried over magnesiumsulfate, and evaporated to give a dark colored gum (33.9 g). The gum wasdispersed in ethyl acetate/hexane (1:3, 150 mL) in the presence ofsilica gel (150 mL). The mixture was filtered, and the filtrate wasconcentrated to give an yellow crystal (20.6 g). Flash silica gel columnchromatography eluting with ethyl acetate-hexane=1-20 to 4-5 afforded(5-bromo-3-pyridinyl)(5-ethyl-1H-pyrrol-2-yl)methanone as a pale yellowsolid (7.11 g).

(5-Bromo-3-pyridinyl)(5-ethyl-1H-pyrrol-2-yl)methanone

NMR (CDCl₃, δ): 1.33 (3H, t, J=7 Hz), 2.75 (2H, q, J=7 Hz), 6.14 (1H,m), 6.83 (1H, m), 8.27 (1H, m), 8.82 (1H, m), 8.98 (1H, m)

MS (ESI⁺): m/z 279 (M+H)

Preparation 165

To a solution of tert-butyl 4-(acetyloxy)-3-oxobutanoate (30.0 g) andethyl 5-iodopentanoate (35.5 g) in N,N-dimethylformamide (150 mL) wasadded potassium carbonate (19.2 g) at room temperature. After stirringfor 4 hours, the mixture was quenched by adding 1N hydrochloric acid(140 mL) under an ice-bath. The mixture was partitioned between ethylacetate (450 mL) and water (300 mL). The organic extract was washed withwater (500 mL, three times) and brine, dried over magnesium sulfate, andevaporated to give a brown oil containing 1-tert-butyl 7-ethyl2-[(acetyloxy)acetyl]heptanedioate (63.4 g, 43% wt purity).

1-tert-Butyl 7-ethyl 2-[(acetyloxy)acetyl]heptanedioate

NMR (CDCl₃, δ): 1.20-1.37 (5H, m), 1.46 (9H, s), 1.63 (2H, m), 1.85 (2H,m), 2.17 (3H, s), 2.30 (2H, t, J=7 Hz), 3.39 (1H, t, J=7 Hz), 4.11 82H,q, J=7 Hz), 4.73 (1H, d, J=17 Hz), 4.82 (1H, d, J=17 Hz)

Preparation 166

To a solution of ethyl thiophene (2.00 g) and ethyl7-chloro-7-oxoheptanoate (5.39 g) in dichloromethane (20 mL) was added 1M tin chloride in dichloromethane (38.9 mL) over 0.5 hour under anice-bath (5 to 8° C.). After stirring for 0.5 hour, the mixture wasstirred for 0.5 hour at room temperature. The mixture was poured intoice-water (100 mL), and extracted with ethyl acetate (100 mL). Theorganic extract was washed with water (100 mL) and brine, dried overmagnesium sulfate, and evaporated to give a brown oil. Flash silica gelcolumn chromatography eluting with ethyl acetate-hexane=1-10 to 3-10afforded ethyl 7-oxo-7-(2-thienyl)heptanoate as a brown oil (5.79 g).

Ethyl 7-oxo-7-(2-thienyl)heptanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.42 (2H, m), 1.63-1.72 (4H, m),2.31 (2H, t, J=7 Hz), 2.91 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 7.13(1H, m), 7.612 (1H, m), 7.70 (1H, m)

The following compounds were obtained in substantially the same manneras those of Preparations 129 and 130.

Preparation 167

tert-Butyl 3-(3,5-dimethyl-4-isoxazolyl)-3-oxopropanoate

NMR (CDCl₃, δ): 1.47 (9H, s), 2.46 (3H, s), 2.68 (3H, s), 3.68 (2H, s)

Preparation 168

Ethyl 4-methyl-3-oxopentanoate

NMR (CDCl₃, δ): 1.14 (6H, d, J=7 Hz), 1.28 (3H, t, J=7 Hz), 2.71 (1H,quintet, J=7 Hz), 3.50 (s, 2H), 4.19 (2H, q, J=7 Hz), 7.06-7.18, 7.56,and 7.85 (4H, m)

Preparation 169

tert-Butyl 4-(methylthio)-3-oxobutanoate

NMR (CDCl₃, δ): 1.47 (9H, s), 2.07 (3H, s), 3.31 (2H, s), 3.58 (2H, s)

Preparation 170

tert-Butyl 3-(1,3-oxazol-5-yl)-3-oxopropanoate

NMR (CDCl₃, δ): (a mixture of keto- and enol-form); keto-form: 1.45 (9H,s), 3.77 (2H, s), 7.85 (1H, s), 8.04 (1H, s); enol-form: d 1.45 (9H, s),5.54 (1H, s), 7.53 (1H, s), 7.91 (1H, s)

The following compounds were obtained in substantially the same manneras that of Preparation 143.

Preparation 171

(2-Chloro-4-pyridinyl)(5-ethyl-1H-pyrrol-2-yl)methanone

NMR (CDCl₃, δ): 1.32 (3H, t, J=7 Hz), 2.74 (2H, q, J=7 Hz), 6.13 (1H,m), 6.79 (1H, m), 7.56 (1H, d, J=5 Hz), 7.69 (1H, s), 8.54 (1H, d, J=5Hz), 9.40 (1H, br)

Preparation 172

(5-Ethyl-1H-pyrrol-2-yl)(3-methoxyphenyl)methanone

NMR (CDCl₃, δ): 1.32 (3H, t, J=7 Hz), 2.74 (2H, q, J=7 Hz), 3.87 (3H,s), 6.08 (1H, m), 6.83 (1H, m), 7.08 (1H, dd, J=2 Hz, 8 Hz), 7.33-7.42(2H, m), 7.47 (1H, d, J=8 Hz), 9.58 (1H, br)

MS (ESI⁺): m/z 230

Preparation 173

(5-Ethyl-1H-pyrrol-2-yl)(4-pyridinyl)methanone

NMR (CDCl₃, δ): 1.32 (3H, t, J=7 Hz), 2.72 (2H, q, J=7 Hz), 6.13 (1H,m), 6.81 (1H, m), 7.65 (2H, d, J=7 Hz), 8.77 (2H, d, J=7 Hz), 9.39 (1H,br)

Preparation 174

(5-Ethyl-1H-pyrrol-2-yl)(2-pyrazinyl)methanone

NMR (CDCl₃, δ): 1.33 (3H, t, J=7 Hz), 2.77 (2H, q, J=7 Hz), 6.14 (1H,m), 7.51 (1H, m), 8.65 (1H, m), 8.74 (1H, m), 9.36 (1H, br)

Preparation 175

(5-Ethyl-1H-pyrrol-2-yl)(3-pyridinyl)methanone

NMR (CDCl₃, δ): 1.33 (3H, t, J=7 Hz), 2.76 (2H, q, J=7 Hz), 6.12 (1H,m), 6.81 (1H, m), 7.42 (1H, m), 8.13 (1H, m), 8.76 (1H, m), 9.08 (1H,m), 9.36 (1H, br)

Preparation 176

A mixture of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile(300 mg), methanesulfonylacetic acid (208 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (361 mg),and 1-hydroxybenzotriazole (254 mg) in N,N-dimethylformamide (1 mL) wasstirred for 1.5 hours. The mixture was partitioned between ethyl acetateand water. The organic layer was washed with water two times, saturatedsodium bicarbonate, and brine, dried over magnesium sulfate, andevaporated to give a pale brown solid. Flash silica gel columnchromatography eluting with ethyl acetate-hexane=1/2 to 1/0 affordedN-[2-(3-cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]-2-(methylsulfonyl)acetamideas a pale brown foam, which was solidified upon standing (505 mg).

N-[2-(3-Cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]-2-(methylsulfonyl)acetamide

NMR (CDCl₃, δ): 1.29 (3H, t, J=7 Hz), 2.62 (2H, q, J=7 Hz), 3.28 (3H,s), 4.15 (2H, s), 6.12 (1H, d, J=5 Hz), 6.75 (1H, d, J=5 Hz), 7.58 (1H,t, J=9 Hz), 7.82 (1H, d, J=9 Hz), 8.01 (1H, d, J=9 Hz), 8.06 (1H, s)

The following compound was obtained in substantially the same manner asthat of Preparation 176.

Preparation 177

Ethyl3-{[2-(4-cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]amino}-3-oxopropanoate

NMR (CDCl₃, δ): 1.20-1.37 (6H, m), 2.56 (2H, q, J=7 Hz), 3.57 (2H, s),4.30 (2H, q, J=7 Hz), 6.06 (1H, d, J=5 Hz), 6.68 (1H, d, J=5 Hz), 7.54(2H, d, J=9 Hz), 7.84 (2H, d, J=9 Hz)

EXAMPLE 1

To a solution of4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (100 mg) intoluene (1 mL) were added 1-(4-methoxyphenyl)acetone (103 mg) andp-toluene-sulfonic acid monohydrate (16 mg) at ambient temperature. Thereaction mixture was heated at 80° C. for 3 hours. The mixture wasevaporated in vacuo. The residue was purified by flash silica gel columnchromatography eluting with hexane-ethyl acetate 20-1 and 15-1 to give4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile(31 mg, 20.2%) as an yellow solid.

4-[7-Ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.40 (3H, t, J=8 Hz), 2.31 (3H, s), 3.16 (2H, q, J=8Hz), 3.77 (3H, s), 6.10 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 6.75 (2H,d, J=8 Hz), 6.93 (2H, d, J=8 Hz), 7.33 (2H, d, J=8 Hz), 7.53 (2H, d, J=8Hz)

MS (ESI⁺): m/z 368 (M+H)

The following compounds were obtained in substantially the same manneras that of Example 1.

EXAMPLE 2 Ethyl4-(4-cyanophenyl)-2-(2-ethoxy-2-oxoethyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (CDCl₃, δ): 0.84 (3H, t, J=7 Hz), 1.28 (3H, t, J=7 Hz), 1.37 (3H, t,J=7 Hz), 3.04 (2H, q, J=7 Hz), 3.93 (2H, q, J=7 Hz), 4.13 (3H, s), 4.19(2H, q, J=7 Hz), 6.24 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz), 7.13 (2H,d, J=9 Hz), 7.76 (2H, d, J=9 Hz)

EXAMPLE 3 Ethyl4-(4-cyanophenyl)-7-ethyl-2-(trifluoromethyl)pyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (CDCl₃, δ): 1.08 (3H, t, J=7 Hz), 1.41 (3H, t, J=7 Hz), 3.11 (2H, q,J=7 Hz), 4.11 (2H, q, J=7 Hz), 6.43 (1H, d, J=5 Hz), 6.93 (1H, d, J=5Hz), 7.62 (2H, d, J=9 Hz), 7.80 (2H, d, J=9 Hz)

EXAMPLE 44-[7-Ethyl-2-methyl-3-(3-pyridinylcarbonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.43 (t, J=7 Hz, 3H), 2.47 (s, 3H), 3.09 (q, J=7 Hz,2H), 6.35 (d, J=5 Hz, 1H), 6.74 (d, J=5 Hz, 1H), 7.23 (1H, m), 7.48 (2H,d, J=9 Hz), 7.55 (2H, d, J=9 Hz), 7.93 (1H, m), 8.62 (1H, m), 8.74 (1H,m)

EXAMPLE 53-[7-Ethyl-2-methyl-3-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.42 (3H, t, J=7 Hz), 2.32 (3H, s), 3.08 (2H, q, J=7Hz), 6.15 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.00 (2H, d, J=9 Hz),7.37 (2H, m), 7.57 (2H, m), 8.50 (2H, d, J=9 Hz)

EXAMPLE 64-(3-Benzyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile

NMR (CDCl₃, δ): 1.40 (3H, t, J=8 Hz), 2.35 (3H, s), 3.04 (2H, q, J=8Hz), 3.83 (3H, s), 5.94 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 6.98 (2H,d, J=8 Hz), 7.14-7.30 (3H, m), 7.46 (2H, d, J=8 Hz), 7.68 (2H, d, J=8Hz)

MS (ESI⁺): m/z 352 (M+H)

EXAMPLE 74-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-3-carbonitrile

mp: 172-173° C.

NMR (CDCl₃, δ): 1.41 (3H, t, J=8 Hz), 3.10 (2H, q, J=8 Hz), 6.65 (1H, d,J=5 Hz), 6.88 (1H, d, J=5 Hz), 7.47-7.64 (6H, m), 7.70 (1H, br s),7.81-7.90 (2H, m)

EXAMPLE 83-(3-Ethyl-7,7,9,9-tetramethyl-6,7,8,9-tetrahydropyrrolo[1,2-b]cinnolin-10-yl)benzonitrile

NMR (CDCl₃, δ): 1.00-1.15 (12H, m), 1.37 (3H, t, J=8 Hz), 2.81 (3H, s),3.00 (2H, q, J=8 Hz), 3.82 (2H, t, J=5 Hz), 5.46 (1H, d, J=5 Hz), 6.46(1H, d, J=5 Hz), 7.50-7.65 (3H, m), 7.72 (1H, m)

EXAMPLE 93-(3-Ethyl-9-oxo-6,7,8,9-tetrahydropyrrolo[1,2-b]cinnolin-10-yl)benzonitrile

NMR (CDCl₃, δ): 1.40 (3H, t, J=8 Hz), 2.08-2.22 (2H, m), 2.60 (2H, t,J=7 Hz), 3.00-3.15 (4H, m), 6.26 (1H, d, J=5 Hz), 6.74 (1H, d, J=5 Hz),7.49-7.61 (3H, m), 7.74 (1H, m)

MS (ESI⁺): m/z 316 (M+H)

EXAMPLE 103-(6-Ethyl-1-oxo-2,3-dihydro-1H-cyclopenta[e]pyrrolo[1,2-b]pyridazin-9-yl)benzonitrile

mp: 150-154° C.

NMR (CDCl₃, δ): 1.43 (3H, t, J=8 Hz), 2.75 (2H, t, J=7 Hz), 3.10 (2H, q,J=8 Hz), 3.24 (2H, t, J=7 Hz), 6.67 (1H, d, J=5 Hz), 6.87 (1H, d, J=5Hz), 7.60 (1H, t, J=8 Hz), 7.75-7.90 (3H, m)

MS (ESI⁺): m/z 324 (M+Na)

EXAMPLE 113-(7-Ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile

NMR (CDCl₃, δ): 1.05 (9H, s), 1.39 (3H, t, J=8 Hz), 2.68 (2H, s), 3.04(2H, q, J=8 Hz), 6.36 (1H, s), 6.48 (1H, d, J=5 Hz), 6.67 (1H, d, J=5Hz), 7.51 (1H, t, J=8 Hz), 7.75 (1H, br d, J=8 Hz), 7.92-8.01 (2H, m)

MS (ESI⁺): m/z 318 (M+H)

EXAMPLE 123-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.44 (3H, t, J=8 Hz), 3.11 (2H, q, J=8 Hz), 6.52-6.60(2H, m), 6.74 (1H, d, J=5 Hz), 6.98 (1H, s), 7.09 (1H, d, J=5 Hz),7.56-7.68 (2H, m), 7.78 (1H, dd, J=8, 1 Hz), 7.96-8.08 (2H, m)

MS (ESI⁺): m/z 314 (M+H)

EXAMPLE 134-[7-Ethyl-2-methyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.38 (3H, t, J=8 Hz), 2.89 (3H, s), 3.00-3.11 (5H, m),6.09 (1H, d, J=5 Hz), 6.73 (1H, d, J=5 Hz), 7.45 (2H, d, J=8 Hz), 7.76(2H, d, J=8 Hz)

MS (ESI⁺): m/z 340 (M+H)

EXAMPLE 13-24-{7-Ethyl-2-[(methylsulfonyl)methyl]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrile

NMR (CDCl₃, δ): 1.39 (3H, t, J=8 Hz), 2.96-3.09 (5H, m), 4.44 (2H, s),6.63 (1H, d, J=5 Hz), 6.71 (1H, s), 6.81 (1H, d, J=5 Hz), 7.79 (2H, d,J=8 Hz), 7.85 (2H, d, J=8 Hz)

MS (ESI⁺): m/z 340 (M+H)

EXAMPLE 153-[7-Ethyl-2-methyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.39 (3H, t, J=8 Hz), 2.89 (3H, s), 3.00-3.11 (5H, m),6.09 (1H, d, J=5 Hz), 6.73 (1H, d, J=5 Hz), 7.54-7.63 (3H, m), 7.77 (1H,m)

EXAMPLE 16

To a solution of4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile(22 mg) in N,N-dimethylformamide (1 mL) were added 1N sodium hydroxide(0.12 mL) and 30% hydrogen peroxide (0.07 mL) at ambient temperature.After 1 hour stirring, the reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with water threetimes and brine, dried over magnesium sulfate, and evaporated in vacuo.The residue was purified by flash silica gel column chromatography(silica gel, 30 mL) eluting with hexane-ethyl acetate=5-1 and 0-1 togive4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzamide(18 mg, 78.0%) as an yellow solid.

4-[7-Ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzamide

NMR (CDCl₃, δ): 1.41 (3H, t, J=8 Hz), 2.31 (3H, s), 3.17 (2H, q, J=8Hz), 3.77 (3H, s), 5.61 (0.2H, br s), 6.02 (0.4H, br s), 6.13 (1H, d,J=5 Hz), 6.60 (1H, d, J=5 Hz), 6.75 (2H, d, J=8 Hz), 6.95 (2H, d, J=8Hz), 7.31 (2H, d, J=8 Hz), 7.68 (2H, d, J=8 Hz)

MS (ESI⁺): m/z 386 (M+H)

The following compound was obtained in substantially the same manner asthat of Example 16.

EXAMPLE 17[2-(Dimethylamino)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide

NMR (CDCl₃, δ): 1.32 (3H, t, J=7 Hz), 2.90 (6H, s), 2.95 (2H, q, J=7Hz), 3.36 (3H, s), 6.21 (1H, d, J=5 Hz), 6.79 (1H, d, J=5 Hz), 7.44 (1H,s, br), 7.52-7.56 (2H, m), 7.90 (1H, s), 7.94-8.06 (2H, m)

MS (ESI⁺): m/z 387 (M+H)

EXAMPLE 18 3-(7-Ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzamide

NMR (CDCl₃, δ): 1.05 (9H, s), 1.39 (3H, t, J=8 Hz), 2.68 (2H, s), 3.04(2H, q, J=8 Hz), 5.70 (1H, br s), 6.11 (1H, br s), 6.41 (1H, s), 6.52(1H, d, J=5 Hz), 6.65 (1H, d, J=5 Hz), 7.59 (1H, t, J=8 Hz), 7.85-7.93(2H, m), 8.15 (1H, br s)

MS (ESI⁺): m/z 336 (M+H)

EXAMPLE 19 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide

NMR (CDCl₃, δ): 1.43 (3H, t, J=8 Hz), 3.10 (2H, q, J=8 Hz), 5.70 (1H, brs), 6.13 (1H, br s), 6.53-6.60 (2H, m), 6.71 (1H, d, J=5 Hz), 7.02 (1H,s), 7.06 (1H, d, J=5 Hz), 7.55-7.65 (2H, m), 7.79-7.98 (2H, m), 8.02(1H, br s)

MS (ESI⁺): m/z 332 (M+H)

EXAMPLE 205-[2-({[4-(Aminocarbonyl)benzyl,]oxy}methyl)-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (DMSO-d₆, δ): 1.27-1.45 (7H, m), 1.99 (2H, m), 2.96 (2H, m), 3.40(2H, m), 4.67 (2H, s), 4.72 (2H, s), 5.88 (1H, d, J=5 Hz), 6.67 (1H, d,J=5 Hz), 7.35 (1H, s, br), 7.44 (2H, d, J=8 Hz), 7.86 (2H, d, J=8 Hz),7.96 (1H, s, br), 8.21 (1H, m), 8.60 (1H, m), 8.86 (1H, m)

EXAMPLE 21

To a solution of ethyl 6-(3-cyanobenzoyl)-7-oxooctanoate (3.18 g) intoluene (30 mL) was added 2-ethyl-1H-pyrrol-1-amine (1.17 g) andp-toluenesulfonic acid monohydrate (96 mg) at ambient temperature. Thereaction mixture was refluxed for 1 hour. The mixture was evaporated invacuo. The residue was purified by flash silica gel chromatography(silica gel, 200 mL) eluting with hexane-ethyl acetate=20-1, 15-1, and10-1 to give ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate(3.29 g, 83.8%) as an yellow oil.

Ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=8 Hz), 1.32-1.58 (7H, m), 2.18 (2H, t,J=8 Hz), 2.35-2.45 (2H, m), 3.01 (2H, q, J=8 Hz), 4.10 (2H, q, J=8 Hz),5.79 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.57-7.67 (3H, m), 7.75 (1H,m)

The following compounds were obtained in substantially the same manneras that of Example 21.

EXAMPLE 22 Ethyl 2,4-diisopropylpyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (300 MHz, CDCl₃, δ): 1.32 (6H, d, J=7.5 Hz), 1.39 (3H, t, J=75 Hz),1.46 (6H, d, J=75 Hz), 2.91-3.05 (1H, m), 3.05-3.20 (1H, m), 4.38 (2H,q, J=75 Hz), 6.64-6.68 (1H, m), 6.76-6.80 (1H, m), 7.65-7.68 (1H, m)

MS (ES+) m/e 275.33

EXAMPLE 23 Ethyl4-(2-chlorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (300 MHz, CDCl₃, δ): 0.89 (3H, t, J=7.5 Hz), 1.30-1.40 (6H, m),3.36-3.51 (1H, m), 4.00 (2H, q, J=7.5 Hz), 6.10-6.18 (1H, m), 6.75-6.84(1H, m), 7.28-7.45 (3H, m), 7.45-7.55 (1H, m), 7.75-7.81 (1H, m)

EXAMPLE 24 Ethyl2-isopropyl-4-(2-naphthyl)pyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (300 MHz, CDCl₃, δ): 0.78 (3H, t, J=7.5 Hz), 1.38 (6H, d, J=75 Hz),3.24-3.35 (1H, m), 3.95 (2H, q, J=7.5 Hz), 6.36-6.40 (1H, m), 6.80-6.85(1H, m), 7.50-7.54 (3H, m), 7.78-7.82 (1H, m), 7.82-8.00 (4H, m)

MS (ES+) m/e 359.56

EXAMPLE 25 Ethyl5-{7-ethyl-2-methyl-4-[3-(trifluoromethyl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

NMR (CDCl₃, δ): 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.59(4H, m), 2.14 (2H, t, J=7 Hz), 2.38-2.46 (2H, m), 2.55 (3H, s), 3.01(2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.83 (1H, d, J=4 Hz), 6.51 (1H,d, J=4 Hz), 7.53-7.64 (3H, m), 7.71 (1H, d, J=8 Hz)

MS (ESI⁺): m/z 433 (M+H)

EXAMPLE 26 Ethyl5-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.38-1.60(4H, m), 2.18 (2H, t, J=7 Hz), 2.42 (3H, s), 2.38-2.50 (2H, m), 2.55(3H, s), 3.00 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 5.87 (1H, d, J=4Hz), 6.51 (1H, d, J=4 Hz), 7.50 (1H, s), 8.39 (1H, s), 8.53 (1H, s)

MS (ESI⁺): m/z 380 (M+H)

EXAMPLE 27 Ethyl5-[7-ethyl-4-(3-methoxy-5-isoxazolyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.55-1.64(2H, m), 1.64-1.80 (2H, m), 2.33 (2H, t, J=7 Hz), 2.74-2.85 (2H, m),3.03 (2H, q, J=7 Hz), 3.43 (3H, s), 4.08 (3H, s), 4.12 (2H, q, J=7 Hz),4.62 (2H, s), 6.28 (1H, s), 6.38 (1H, d, J=4 Hz), 6.65 (1H, d, J=4 Hz)

MS (ESI⁺): m/z 416 (M+H)

EXAMPLE 28 Ethyl5-{7-ethyl-2-methyl-4-[3-(1,3-oxazol-5-yl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

NMR (CDCl₃, δ): 1.20 (3H, t, J=7 Hz), 1.35 (3H, t, J=7 Hz), 1.40-1.63(4H, m), 2.17 (2H, t, J=7 Hz), 2.44-2.57 (2H, m), 2.56 (3H, s), 3.02(2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.89 (1H, d, J=4 Hz), 6.50 (1H,d, J=4 Hz), 7.33 (1H, d, J=8 Hz), 7.39 (1H, s), 7.53 (1H, t, J=8 Hz),7.66 (1H, m), 7.74 (1H, d, J=8 Hz), 7.93 (1H, s)

EXAMPLE 29 Ethyl5-[4-(3,4-dichlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.38-1.48(2H, m), 1.50-1.65 (2H, m), 2.20 (2H, t, J=7 Hz), 2.38-2.47 (2H, m),2.54 (3H, s), 3.00 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.87 (1H, d,J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.19 (1H, dd, J=2 Hz, 8 Hz), 7.46 (1H, d,J=2 Hz), 7.56 (1H, d, J=8 Hz)

MS (ESI⁺): m/z 433 (M+H)

EXAMPLE 30 Ethyl5-[4-(4-chloro-2-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.44-1.67(4H, m), 2.15-2.26 (2H, m), 2.42-2.56 (2H, m), 2.56 (3H, s), 3.01 (2H,q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.95 (1H, d, J=3 Hz), 6.54 (1H, d, J=3Hz), 7.40 (1H, dd, J=2 Hz, 4 Hz), 7.54 (1H, d, J=2 Hz), 8.67 (1H, d, J=4Hz)

MS (ESI⁺): m/z 400 (M+H)

EXAMPLE 31 Ethyl5-[4-(5-chloro-2-thienyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.48-1.74(4H, m), 2.28 (2H, t, J=7 Hz), 2.68-2.77 (2H, m), 3.02 (2H, q, J=7 Hz),3.44 (3H, s), 4.12 (2H, q, J=7 Hz), 4.60 (2H, s), 6.25 (1H, d, J=4 Hz),6.60 (1H, d, J=4 Hz), 6.97 (2H, m)

MS (ESI⁺): m/z 435 (M+H)

EXAMPLE 32 Ethyl5-[7-ethyl-4-(6-methoxy-2-pyrazinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.52-1.68(4H, m), 2.23 (2H, t, J=7 Hz), 2.48-2.55 (2H, m), 2.56 (3H, s), 3.02(2H, q, J=7 Hz), 3.98 (3H, s), 4.09 (2H, q, J=7 Hz), 6.03 (1H, d, J=4Hz), 6.55 (1H, d, J=4 Hz), 8.30 (1H, s), 8.33 (1H, s)

MS (ESI⁺): m/z 397 (M+H)

EXAMPLE 33 Ethyl5-[4-(1-benzofuran-2-yl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.62-1.83(4H, m), 2.33 (2H, t, J=7 Hz), 2.57 (3H, s), 2.69-2.78 (2H, m), 3.03(2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 6.48 (1H, d, J=4 Hz), 6.59 (1H,d, J=4 Hz), 7.15 (1H, s), 7.26-7.42 (2H, m), 7.57 (1H, d, J=8 Hz), 7.68(1H, d, J=8 Hz)

MS (ESI⁺): m/z 405 (M+H)

EXAMPLE 34 Ethyl5-[4-(1-benzothien-2-yl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.21 (3H, t, J=7 Hz), 1.35 (3H, t, J=7 Hz), 1.52-1.69(4H, m), 2.23 (2H, t, J=7 Hz), 2.56 (3H, s), 2.61-2.70 (2H, m), 3.02(2H, q, J=7 Hz), 4.07(2H, q, J=7 Hz), 6.21 (1H, d, J=4 Hz), 6.53 (1H, d,J=4 Hz), 7.35-7.43 (3H, m), 7.81-7.92 (2H, m)

EXAMPLE 35 Ethyl5-[7-ethyl-2-methyl-4-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.53-1.66(2H, m), 1.66-1.83 (2H, m), 2.34 (2H, t, J=7 Hz), 2.56 (3H, s),2.62-2.73 (2H, m), 3.02 (2H, q, J=7 Hz), 4.13 (2H, q, J=7 Hz), 6.42 (1H,d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.50 (1H, s), 8.10 (1H, s)

MS (ESI⁺): m/z 356 (M+H)

EXAMPLE 36 Ethyl5-(7-ethyl-2-methyl-4-phenylpyrrolo[1,2-b]pyridazin-3-yl)pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60(4H, m), 2.15 (2H, t, J=7 Hz), 2.41-2.48 (2H, m), 2.55 (3H, s), 3.02(2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 5.88 (1H, d, J=4 Hz), 6.48 (1H,d, J=4 Hz), 7.31-7.34 (2H, m), 7.40-7.49 (3H, m)

MS (ESI⁺): m/z 365 (M+H)

EXAMPLE 37 Ethyl5-[7-ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.18 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.39-1.55(4H, m), 2.14 (2H, d, J=7 Hz), 2.44-2.55 (2H, m), 2.58 (3H, s), 3.03(2H, q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 5.86 (1H, d, J=4 Hz), 6.51 (1H,d, J=4 Hz), 7.45-7.52 (1H, m), 7.69 (1H, dd, J=2 Hz, 8 Hz), 7.84 (1H, d,J=2 Hz), 8.20 (2H, d, J=8 Hz), 9.00 (1H, m)

EXAMPLE 38 Ethyl7-{4-[4-({[(benzyloxy)carbonyl]amino}sulfonyl)pbenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoate

NMR (CDCl₃, δ): 1.12-1.23 (7H, m), 1.33-1.51 (7H, s), 2.17 (2H, t, J=7Hz), 2.35 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 4.11 (2H, q, J=7Hz), 5.17 (2H, s), 5.78 (1H, d, J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.29-7.38(5H, m), 7.49 (2H, d, J=9 Hz), 7.87 (1H, s, br), 8.11 (2H, d, J=9 Hz)

MS (ESI⁺): m/z 606 (M+H)

MS (ESI⁻): m/z 604 (M−H)

EXAMPLE 392-{[4-(3-Chlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methyl}-1,3-propanediol

NMR (CDCl₃, δ): 1.26 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.64-1.82(3H, m), 2.59 (3H, s), 3.02 (2H, q, J=7 Hz), 3.45 (2H, m), 3.63 (2H, m),4.12 (2H, q, J=7 Hz), 5.93 (1H, d), J=5 Hz), 6.53 (1H, d, J=5 Hz), 7.28(1H, m), 7.42-7.44 (3H, m)

EXAMPLE 40 Ethyl5-{7-ethyl-2-methyl-4-[3-(methylsulfonyl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

NMR (CDCl₃, δ): 1.22 (3H, t, J=8 Hz), 1.33-1.57 (7H, m), 2.18 (2H, t,J=8 Hz), 2.35-2.45 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 3.12(3H, s), 4.08 (2H, q, J=8 Hz), 5.80 (1H, d, J=5 Hz), 6.51 (1H, d, J=5Hz), 7.64-7.74 (2H, m), 7.96 (1H, br s), 8.04 (1H, m)

MS (ESI⁺): m/z 443 (M+H)

EXAMPLE 41 Ethyl5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=8 Hz), 1.30-1.62 (7H, m), 2.21 (2H, t,J=8 Hz), 2.35-2.45 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=8 Hz), 4.10(2H, q, J=8 Hz), 5.85 (1H, d, J=5 Hz), 6.53 (1H, d, J=5 Hz), 7.24 (1H,dd, J=7, 1 Hz), 7.35 (1H, br s), 8.53 (1H, d, J=7 Hz)

MS (ESI⁺): m/z 400 (M+H)

EXAMPLE 42 Ethyl5-[7-ethyl-2-methyl-4-(3-nitrophenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.21 (3H, t, J=8 Hz), 1.34-1.59 (7H, m), 2.17 (2H, t,J=8 Hz), 2.37-2.47 (2H, m), 2.57 (3H, s), 3.01 (2H, q, J=8 Hz), 4.08(2H, q, J=8 Hz), 5.81 (1H, d, J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.64-7.74(2H, m), 8.25 (1H, br s), 8.33 (1H, m)

MS (ESI⁺): m/z 410 (M+H)

EXAMPLE 43 Ethyl4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (CDCl₃, δ): 0.98 (3H, t, J=8 Hz), 2.55 (3H, s), 4.05 (2H, q, J=8Hz), 6.35 (1H, m), 6.81 (1H, m), 7.12-7.22 (2H, m), 7.41-7.50 (2H, m),7.76 (1H, m)

MS (ESI⁺): m/z 359 (M+H)

EXAMPLE 444-(3-Butyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile

NMR (CDCl₃, δ): 0.78 (3H, t, J=8 Hz), 1.12-1.43 (7H, m), 2.31-2.40 (2H,m), 2.56 (3H, s), 3.00 (2H, q, J=8 Hz), 5.79 (1H, d, J=5 Hz), 6.50 (1H,d, J=5 Hz), 7.47 (2H, d, J=8 Hz), 7.77 (2H, d, J=8 Hz)

MS (ESI⁺): m/z 318 (M+H)

EXAMPLE 45 Ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.65(4H, m), 2.21 (2H, t, J=7 Hz), 2.37-2.49 (2H, m), 2.56 (3H, s), 3.00(2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.53 (1H,d, J=4 Hz), 7.85 (1H, m), 8.53 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz)

MS: (m/z) 444, 446 (M+H)

EXAMPLE 46 Ethyl5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylthio)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.40-1.63(4H, m), 2.18 (3H, s), 2.20 (2H, t, J=7 Hz), 2.48-2.58 (2H, m), 3.02(2H, q, J=7 Hz), 3.81 (2H, s), 4.10 (2H, q, J=7 Hz), 5.89 (1H, d, J=4Hz), 6.57 (1H, d, J=4 Hz), 7.27 (1H, m), 7.38 (1H, s), 8.53 (1H, d, J=4Hz)

MS: (m/z) 446 (M+H)

EXAMPLE 47 Ethyl6-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate

NMR (CDCl₃, δ): 1.15-1.29 (5H, m), 1.32-1.61 (7H, m), 2.20 (2H, t, J=8Hz), 2.33-2.43 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 4.10 (2H, q,J=8 Hz), 5.79 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.57-7.67 (3H, m),7.75 (1H, m)

MS (ESI⁺): m/z 404 (M+H)

EXAMPLE 48 Ethyl5-[4-(6-chloro-2-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.46-1.65(4H, m), 2.22 (2H, t, J=7 Hz), 2.46-2.57 (2H, m), 2.54 (3H, s), 3.00(2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 5.95 (1H, d, J=4 Hz), 6.51 (1H,d, J=4 Hz), 7.38-7.47 (2H, m), 7.80 (1H, t, J=8 Hz)

MS (ESI⁺): m/z 400

EXAMPLE 49 Ethyl5-[7-ethyl-4-(3-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.40-1.62(4H, m), 2.17 (2H, t, J=7 Hz), 2.43-2.52 (2H, m), 2.54 (3H, s), 3.00(2H, q, J=7 Hz), 3.83 (3H, s), 4.08 (2H, q, J=7 Hz), 5.91 (1H, d, J=4Hz), 6.49 (1H, d, J=4 Hz), 6.87-6.99 (3H, m), 7.37 (1H, t, J=8 Hz)

MS (ESI⁺): m/z 395

EXAMPLE 50 Ethyl5-[4-(3,5-dichlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.39-1.52(2H, m), 1.52-1.64 (2H, m), 2.22 (2H, t, J=7 Hz), 2.38-2.48 (2H, m),2.54 (3H, s), 3.00 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.88 (1H, d,J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.25 (2H, m), 7.45 (1H, m)

MS (ESI⁺): m/z 433

EXAMPLE 51 Ethyl5-[4-(5-chloro-2-thienyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.46-1.58(2H, m), 1.60-1.74 (2H, m), 2.28 (2H, t, J=7 Hz), 2.53 (3H, s),2.56-2.66 (2H, m), 2.98 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 6.20 (1H,d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 6.94 (1H, d, J=4 Hz), 6.98 (1H, d, J=4Hz)

MS (ESI⁺): m/z 405

EXAMPLE 52 Ethyl5-[7-ethyl-4-(3-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.38-1.50(2H, m), 150-1.63 (2H, m), 2.17 (2H, t, J=7 Hz), 2.39-2.48 (2H, m), 2.54(3H, s), 3.03 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 5.88 (1H, d, J=4Hz), 6.50 (1H, d, J=4 Hz), 7.03-7.16 (3H, m), 7.38-7.47 (1H, m)

MS (ESI⁺): m/z 383

EXAMPLE 53 Ethyl5-[7-ethyl-2-methyl-4-(3-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.18 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.60(4H, m), 2.16 (2H, t, J=7 Hz), 2.44-2.56 (2H, m), 2.59 (3H, s), 3.04(2H, q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 5.89 (1H, d, J=4 Hz), 6.53 (1H,d, J=4 Hz), 7.62 (1H, t, J=8 Hz), 7.80 (1H, t, J=8 Hz), 7.90 (1H, d, J=8Hz), 8.21 (2H, m), 8.90 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 416

EXAMPLE 54 Ethyl5-[7-ethyl-2-methyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.64(4H, m), 2.19 (2H, t, J=7 Hz), 2.38-2.52 (2H, m), 2.55 (3H, s), 3.02(2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 5.83 (1H, d, J=4 Hz), 6.51 (1H,d, J=4 Hz), 7.29 (2H, m), 8.72 (2H, m)

MS (ESI⁺): m/z 366

EXAMPLE 55 Ethyl5-[7-ethyl-4-(3-methoxy-5-isoxazolyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.55-1.82(4H, m), 2.33 (2H, t, J=7 Hz), 2.55 (3H, s), 2.62-2.72 (2H, m), 2.99(2H, q, J=7 Hz), 4.08 (3H, s), 4.12 (2H, q, J=7 Hz), 6.26 (1H, s), 6.34(1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz)

EXAMPLE 56 Ethyl5-[7-ethyl-2-methyl-4-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.50-1.75(4H, m), 2.29 (2H, t, J=7 Hz), 2.55 (6H, s), 2.56-2.65 (2H, m), 2.99(2H, q, J=7 Hz), 4.11 (2H, q, J=7 Hz), 6.16 (1H, d, J=4 Hz), 6.22 (1H,s), 6.54 (1H, d, J=4 Hz)

MS (ESI⁺): m/z 370

EXAMPLE 57 Ethyl5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.36-1.63(4H, m), 2.20 (2H, t, J=7 Hz), 2.48-2.63 (2H, m), 3.03 (2H, q, J=7 Hz),3.45 (3H, s), 4.09 (2H, q, J=7 Hz), 4.62 (2H, s), 5.89 (1H, d, J=4 Hz),6.60 (1H, d, J=4 Hz), 7.26 (1H, m), 7.37 (1H, s), 8.53 (1H, d, J=5 Hz)

MS (ESI⁺): m/z 430

EXAMPLE 58 Ethyl5-[7-ethyl-2-(methoxymethyl)-4-(3-methoxyphenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.63(4H, m), 2.16 (2H, t, J=7 Hz), 2.54-2.65 (2H, m), 3.04 (2H, q, J=7 Hz),3.45 (3H, s), 3.83 (3H, s), 4.08 (2H, q, J=7 Hz), 4.62 (2H, s), 5.96(1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz), 6.87-7.00 (3H, m), 7.38 (1H, t,J=8 Hz)

MS (ESI⁺): m/z 425

EXAMPLE 59 Ethyl5-[7-ethyl-2-(methoxymethyl)-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.17 (3H, t, J=7 Hz), 1.43 (3H, t, J=7 Hz), 1.36-1.58(4H, m), 2.10 (2H, m), 2.56-2.68 (2H, m), 3.07 (2H, q, J=7 Hz), 3.48(3H, s), 4.02 (2H, q, J=7 Hz), 4.66 (2H, s), 5.90 (1H, d, J=4 Hz), 6.56(1H, d, J=4 Hz), 7.45-7.50 (1H, m), 7.72 (1H, dd, J=2 Hz, 8 Hz), 7.86(1H, d, J=2 Hz), 8.16-8.24 (2H, m), 8.98 (1H, m)

EXAMPLE 60 Ethyl5-[7-ethyl-2-(methoxymethyl)-4-(3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.60(4H, m), 2.17 (2H, t, J=7 Hz), 2.52-2.64 (2H, m), 3.04 (2H, q, J=7 Hz),3.46 (3H, s), 4.10 (2H, q, J=7 Hz), 4.63 (2H, s), 5.89 (1H, d, J=4 Hz),6.58 (1H, d, J=4 Hz), 7.42 (1H, m), 7.71 (1H, m), 8.62 (1H, m), 8.70(1H, m)

MS (ESI⁺): m/z 396

EXAMPLE 61 Ethyl5-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.58(4H, m), 2.17 (2H, t, J=7 Hz), 2.51-2.62 (2H, m), 3.03 (2H, q, J=7 Hz),3.45 (3H, s), 4.08 (2H, q, J=7 Hz), 4.61 (2H, s), 5.92 (1H, d, J=4 Hz),6.56 (1H, d, J=4 Hz), 7.25 (1H, m), 7.37 (1H, s), 7.42 (2H, m)

EXAMPLE 62 Ethyl5-[7-ethyl-2-methyl-4-(3-methylphenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60(4H, m), 2.16 (2H, t, J=7 Hz), 2.40 (3H, s), 2.40-2.50 (2H, m), 2.54(3H, s), 3.03 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 5.90 (1H, d, J=4Hz), 6.49 (1H, d, J=4 Hz), 7.10-7.15 (2H, m), 7.24 (1H, m), 7.33 (1H, m)

MS: (m/z) 379 (M+H)

EXAMPLE 65 Ethyl5-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60(4H, m), 2.18 (2H, t, J=7 Hz), 2.42 (3H, s), 2.48-2.63 (2H, m), 3.05(2H, q, J=7 Hz), 3.46 (3H, s), 4.08 (2H, q, J=7 Hz), 4.62 (2H, s), 5.90(1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.51 (1H, s), 8.41 (1H, s), 8.53(1H, s)

MS (ESI⁺): m/z 410

EXAMPLE 66 Ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.65(4H, m), 2.21 (2H, t, J=7 Hz), 2.37-2.49 (2H, m), 2.56 (3H, s), 3.00(2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.53 (1H,d, J=4 Hz), 7.85 (1H, m), 8.53 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 444, 446

EXAMPLE 67 Ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.63(4H, m), 2.19 (2H, t, J=7 Hz), 2.50-2.66 (2H, m), 3.03 (2H, q, J=7 Hz),3.46 (3H, s), 4.10 (2H, q, J=7 Hz), 4.62 (2H, s), 5.91 (1H, d, J=4 Hz),6.60 (1H, d, J=4 Hz), 7.88 (1H, m), 8.55 (1H, d, J=2 Hz), 8.77 (1H, d,J=2 Hz)

MS (ESI⁺): m/z 474, 476

EXAMPLE 68 Ethyl5-[4-(5,6-dichloro-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.36-1.60(4H, m), 2.23 (2H, t, J=7 Hz), 2.37-2.50 (2H, m), 2.55 (3H, s), 3.02(2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.53 (1H,d, J=4 Hz), 7.81 (1H, d, J=2 Hz), 8.30 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 434

EXAMPLE 69 Ethyl4-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.65-1.78 (2H, m), 2.16-2.25 (2H,m), 2.42 (3H, s), 2.53-2.65 (2H, m), 3.04 (2H, q, J=7 Hz), 3.46 (3H, s),4.12 (2H, q, J=7 Hz), 4.67 (2H, m), 5.91 (1H, d, J=4 Hz), 6.58 (1H, d,J=4 Hz), 7.53 (1H, s), 8.43 (1H, s), 8.54 (1H, s)

MS (ESI⁺): m/z 396

EXAMPLE 70 Ethyl3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.35-2.55(2H, m), 2.42 (3H, s), 2.84-2.96 (2H, m), 3.04 (2H, q, J=7 Hz), 3.46(3H, s), 4.08 (2H, q, J=7 Hz), 4.65 (2H, s), 5.91 (1H, d, J=4 Hz), 6.61(1H, d, J=4 Hz), 7.51 (1H, s), 8.41 (1H, s), 8.52 (1H, s)

EXAMPLE 71 Ethyl4-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

NMR (CDCl₃, δ): 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.66-1.82(2H, m), 2.16-2.28 (2H, m), 2.42 (3H, s), 2.44-2.53 (2H, m), 2.59 (3H,s), 3.02 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz),6.53 (1H, d, J=4 Hz), 7.51 (1H, s), 8.41 (1H, d, J=2 Hz), 8.53 (1H, d,J=2 Hz)

MS (ESI⁺): m/z 366

EXAMPLE 72 Ethyl3-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.30-2.43(2H, m), 2.42 (3H, s), 2.58 (3H, s), 2.76-2.86 (2H, m), 3.02 (2H, q, J=7Hz), 4.10 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz),7.48 (1H, s), 8.40 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 352

EXAMPLE 73 Ethyl3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoate

NMR (CDCl₃, δ): 1.21 (3H, t, J=7 Hz), 1.39 (2H, t, J=7 Hz), 2.35 (2H, t,J=7 Hz), 2.58 (3H, s), 2.74-2.83 (2H, m), 3.01 (2H, q, J=7 Hz), 4.08(2H, q, J=7 Hz), 5.89 (1H, d, J=4 Hz), 6.55 (1H, d, J=4 Hz), 7.87 (1H,s), 8.53 (1H, s), 8.79 (1H, s)

MS: (m/z) 416 (M⁺), 418 (M⁺−2), 85(bp)

EXAMPLE 74 Ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=8 Hz), 1.32-1.55 (5H, m), 2.16 (2H, t,J=8 Hz), 2.46-2.57 (2H, m), 3.03 (2H, q, J=8 Hz), 3.46 (3H, s), 4.09(1H, q, J=8 Hz), 4.62 (2H, s), 5.34 (1H, d, J=5 Hz), 6.57 (1H, d, J=5Hz), 7.59-7.64 (2H, m), 7.68 (1H, br s), 7.75 (1H, m)

MS (ESI⁺): 420 (M+H)

EXAMPLE 75 Ethyl5-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.34-1.55 (7H, m), 2.11-2.22 (5H,m), 2.47 (2H, m), 3.02 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 5.29 (2H,s), 5.94 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.88 (1H, m), 8.56 (1H,m), 8.79 (1H, m)

EXAMPLE 76

To a solution of ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate(1.20 g) in ethanol (12 mL) was added 1N sodium hydroxide (4.62 mL) andwas stirred at ambient temperature for 2 hours. The reaction mixture wasacidified with 1N hydrogen chloride and was partitined between ethylacetate and water. The organic layer was washed with water and brine,dried over magnesium sulfate, and evaporated in vacuo. The residue waspurified by flash silica gel chromatography (silica gel, 100 mL) elutedwith hexane-ethyl acetate=3-1, 2-1, and 1-1 to give an yellow solid (846mg). The solid was recrystallized from hexane-ethyl acetate (5-1) togive5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid as a pale yellow crystals (795 mg, 71.4%).

5-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

mp: 109-110° C.

NMR (CDCl3, δ): 1.33-1.60 (7H, m), 2.42 (2H, t, J=8 Hz), 2.34-2.48 (2H,m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 5.80 (1H, d, J=5 Hz), 6.52 (1H,d, J=5 Hz), 7.56-7.64 (2H, m), 7.66 (1H, br s), 7.76 (1H, m)

MS (ESI⁺): m/z 362 (M−H)

The following compounds were obtained in substantially the same manneras that of Example 76.

EXAMPLE 773-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

NMR (CDCl₃, δ): 1.36 (3H, t, J=7H), 1.56 (2H, m), 2.03 (2H, m), 2.79(2H, m), 3.01 (2H, q, J=7 Hz), 6.01 (1H, d, J=5 Hz), 6.63 (1H, d, J=5Hz), 7.27 (1H, m), 7.40-7.53 (8H, m)

EXAMPLE 785-{7-Ethyl-2-methyl-4-[3-(trifluoromethyl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.22 (2H, t,J=7 Hz), 2.38-2.46 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 5.84(1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.53-7.64 (3H, m), 7.72 (1H, d,J=8 Hz)

MS (ESI⁺): m/z 403 (M−H), 405 (M+H)

EXAMPLE 795-[7-Ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.67 (4H, m), 2.22 (2H, t,J=7 Hz), 2.42 (3H, s), 2.35-2.48 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7Hz), 5.83 (1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.53 (1H, s), 8.39 (1H,s), 8.53 (1H, s)

MS (ESI⁺): m/z 352 (M+H)

EXAMPLE 805-[7-Ethyl-4-(3-methoxy-5-isoxazolyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.36 (3H, t, J=7 Hz), 1.58-1.83 (4H, m), 2.38 (2H, t,J=7 Hz), 2.74-2.85 (2H, m), 3.03 (2H, q, J=7 Hz), 3.43 (3H, s), 4.08(3H, s), 4.62 (2H, s), 6.28 (1H, s), 6.41 (1H, d, J=4 Hz), 6.67 (1H, d,J=4 Hz)

MS (ESI⁺): m/z 386 (M−H), 388 (M+H)

EXAMPLE 815-{7-Ethyl-2-methyl-4-[3-(1,3-oxazol-5-yl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

NMR (CDCl₃, δ): 1.38 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.21 (2H, t,J=7 Hz), 2.43-2.53 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J=7 Hz), 5.89(1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.32 (1H, d, J=8 Hz), 7.39 (1H,s), 7.53 (1H, t, J=8 Hz), 7.65 (1H, s), 7.73 (1H, d, J=8 Hz), 7.93 (1H,s)

MS (ESI⁺): m/z 402 (M−H), 404 (M+H)

EXAMPLE 825-[4-(3,4-Dichlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.42-1.65 (4H, m), 2.27 (2H, t,J=7 Hz), 2.38-2.48 (2H, m), 2.54 (3H, s), 3.02 (2H, q, J=7 Hz), 5.87(1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.19 (1H, dd, J=2 Hz, 8 Hz), 7.45(1H, d, J=2 Hz), 7.56 (1H, d, J=8 Hz)

MS (ESI⁺): m/z 403 (M−H), 405 (M+H)

EXAMPLE 835-[4-(4-Chloro-2-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.36 (3H, t, J=7 Hz), 1.47-1.66 (4H, m), 2.24 (2H, t,J=7 Hz), 1.45-2.56 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=7 Hz), 5.94(1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.39 (1H, dd, J=2 Hz, 7 Hz), 7.53(1H, d, J=2 Hz), 8.67 (1H, d, J=7 Hz)

MS (ESI⁺): m/z 372 (M+H)

EXAMPLE 845-[4-(5-Chloro-2-thienyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.36 (3H, t, J=7 Hz), 1.52-1.74 (4H, m), 2.33 (2H, t,J=7 Hz), 2.69-2.78 (2H, m), 3.01 (2H, q, J=7 Hz), 3.44 (3H, s), 4.60(2H, s), 6.25 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 6.97 (2H, m)

MS (ESI⁺): m/z 405 (M−H), 407 (M+H)

EXAMPLE 855-[7-Ethyl-4-(6-methoxy-2-pyrazinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.55-1.69 (4H, m), 2.28 (2H, m),2.52 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J=7 Hz), 3.97 (3H, s), 6.03(1H, d, J=4 Hz), 6.54 (1H, d, J=4 Hz), 8.30 (1H, s), 8.32 (1H, s)

MS (ESI⁺): m/z 369 (M+H)

EXAMPLE 865-[4-(1-Benzofuran-2-yl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.39 (3H, t, J=7 Hz), 1.66-1.86 (4H, m), 2.34-2.47 (2H,m), 2.58 (3H, s), 2.69-2.85 (2H, m), 3.03 (2H, q, J=7 Hz), 6.47 (1H, d,J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.16 (1H, s), 7.26-7.43 (2H, m), 7.57(1H, d, J=8 Hz), 7.68 (1H, d, J=8 Hz)

EXAMPLE 875-[4-(1-Benzothien-2-yl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.53-1.73 (4H, m), 2.30 (2H, t,J=7 Hz), 2.56 (3H, s), 2.62-2.73 (2H, m), 3.02 (2H, q, J=7 Hz), 6.19(1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.34-7.45 (3H, m), 7.79-7.93 (2H,m)

EXAMPLE 885-[7-Ethyl-2-methyl-4-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.57-1.70 (2H, m), 1.70-1.88 (2H,m), 2.43 (2H, t, J=7 Hz), 2.56 (3H, s), 2.66-2.75 (2H, m), 3.02 (2H, q,J=7 Hz), 6.41 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.52 (1H, s), 8.13(1H, s)

MS (ESI⁺): m/z 328 (M+H)

EXAMPLE 895-(7-Ethyl-2-methyl-4-phenylpyrrolo[1,2-b]pyridazin-3-yl)pentanoic acid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.20 (2H, t,J=7 Hz), 2.43-2.52 (2H, m), 2.54 (3H, s), 3.01 (2H, q, J=7 Hz), 5.89(1H, d, J=4 Hz), 6.48 (1H, d, J=4 Hz), 7.33 (2H, m), 7.38-7.52 (3H, m)

MS (ESI⁺): m/z 337 (M+H)

EXAMPLE 905-[7-Ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.39 (3H, t, J=7 Hz), 1.47-1.61 (4H, m), 2.14-2.23 (2H,m), 2.44-2.55 (2H, m), 2.59 (3H, s), 3.05 (2H, q, J=7 Hz), 5.86 (1H, d,J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.49 (1H, m), 7.73 (1H, dd, J=2 Hz, 8Hz), 7.85 (1H, d, J=2 Hz), 8.23 (2H, m), 8.97 (1H, m)

MS (ESI⁺): m/z 386 (M−H), 388 (M+H)

EXAMPLE 917-{4-[4-(Aminosulfonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoicacid

NMR (CDCl₃, δ): 0.98 (2H, m), 1.17-1.48 (9H, m), 2.27 (2H, t, J=7 Hz),2.36 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 5.06 (2H, s, br), 5.84(1H, d, J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.52 (2H, d, J=9 Hz), 8.04 (2H,d, J=9 Hz)

MS (ESI⁺): m/z 444 (M+H)

EXAMPLE 92({[4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-yl]carbonyl}amino)aceticacid

NMR (CDCl₃, δ): 1.41 (3H, t, J=7 Hz), 3.07 (2H, q, J=7 Hz), 3.95 (2H, d,J=5 Hz), 6.02 (1H, t, br, 5 Hz), 6.37 (1H, d, J=5 Hz), 6.50 (1H, m),6.75 (1H, d, J=5 Hz), 7.01 (1H, d, J=7 Hz), 7.37-7.45 (3H, m), 7.51 (1H,m), 7.55 (1H, m)

EXAMPLE 935-{7-Ethyl-2-methyl-4-[3-(methylsulfonyl)phenyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

NMR (CDCl₃, δ): 1.30-1.59 (7H, m), 2.22 (2H, t, J=8 Hz), 2.33-2.49 (2H,m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 3.12 (3H, s), 5.80 (1H, d, J=5Hz), 6.50 (1H, d, J=5 Hz), 7.63-7.74 (2H, m), 7.95 (1H, br s), 8.03 (1H,br d, J=8 Hz)

MS (ESI⁺): m/z 415 (M+H)

EXAMPLE 945-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

mp: 139-140° C.

NMR (CDCl₃, δ): 1.32-1.64 (7H, m), 2.28 (2H, t, J=8 Hz), 2.36-2.46 (2H,m), 2.55 (3H, s), 3.00 (2H, q, J=8 Hz), 5.85 (1H, d, J=5 Hz), 6.52 (1H,d, J=5 Hz), 7.24 (1H, br d, J=7 Hz), 7.36 (1H, br s), 8.53 (1H, d, J=7Hz)

MS (ESI⁺): m/z 372 (M+H)

EXAMPLE 955-[7-Ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.36 (3H, t, J=8 Hz), 1.40-1.62 (4H, m), 2.25 (2H, t,J=8 Hz), 2.35-2.47 (2H, m), 2.56 (3H, s), 3.00 (2H, q, J=8 Hz), 5.54(1H, d, J=10 Hz), 5.86 (1H, d, J=5 Hz), 6.23 (1H, d, J=16 Hz), 6.51 (1H,d, J=5 Hz), 6.88 (1H, dd, J=16, 10 Hz), 7.20 (1H, dd, J=6, 1 Hz), 7.38(1H, br s), 8.70 (1H, d, J=6 Hz)

EXAMPLE 965-[7-Ethyl-2-methyl-4-(3-nitrophenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=8 Hz), 1.41-1.59 (4H, m), 2.23 (2H, t,J=8 Hz), 2.37-2.47 (2H, m), 2.57 (3H, s), 3.02 (2H, q, J=8 Hz), 5.81(1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.63-7.74 (2H, m), 8.25 (1H, brs), 8.32 (1H, m)

EXAMPLE 97{[7-Ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methoxy}aceticacid

NMR (CDCl₃, δ): 1.33-1.45 (9H, m), 3.04 (2H, q, J=8 Hz), 3.43 (1H, m),4.01 (2H, s), 4.45 (2H, s), 6.09 (1H, d, J=5 Hz), 6.58 (1H, d, J=5 Hz),7.13-7.22 (2H, m), 7.40-7.49 (2H, m)

EXAMPLE 985-[4-(5-Acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.43-1.63 (4H, m), 2.23 (2H, t,J=7 Hz), 2.35-2.48 (2H, m), 2.57 (3H, s), 2.69 (3H, s), 3.03 (2H, q, J=7Hz), 5.80 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 8.26 (1H, m), 8.78 (1H,d, J=2 Hz), 9.23 (1H, d, J=2 Hz)

MS: (m/z) 378 (M−H), 380 (M+H)

EXAMPLE 995-{4-(2-Chloro-4-pyridinyl)-7-ethyl-2-[(methylthio)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

NMR (CDCl₃, δ): 1.36 (3H, t, J=7 Hz), 1.42-1.65 (4H, m), 2.18 (3H, s),2.28 (2H, t, J=7 Hz), 2.48-2.60 (2H, m), 3.02 (2H, q, J=7 Hz), 3.81 (2H,s), 5.89 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.27 (1H, m), 7.38 (1H,s), 8.53 (1H, d, J=5 Hz)

MS: (m/z) 416 (M−H), 418 (M+H)

EXAMPLE 1005-{4-(2-Chloro-4-pyridinyl)-7-ethyl-2-[(methylsulfonyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.29 (2H, t,J=7 Hz), 2.56-2.67 (2H, m), 2.98 (2H, q, J=7 Hz), 3.13 (3H, s), 4.54(2H, s), 5.98 (1H, d, J=4 Hz), 6.69 (1H, d, J=4 Hz), 7.27 (1H, m), 7.38(1H, s), 8.56 (1H, d, J=5 Hz)

MS: (m/z) 448 (M−H), 450 (M+H)

EXAMPLE 1015-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.03-1.45 (4H, m), 1.36 (3H, t, J=7 Hz), 1.97 (2H, t,J=7 Hz), 2.36-2.48 (2H, m), 3.02 (2H, q, J=7 Hz), 5.96 (1H, d, J=4 Hz),6.64 (1H, d, J=4 Hz), 7.31 (1H, d, J=5 Hz), 7.39-7.53 (6H, m), 8.55 (1H,d, J=5 Hz)

EXAMPLE 1025-[4-(6-Chloro-2-pyridinyl)-7-ethyl-2-methylpyrrolo-[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.36 (3H, t, J=7 Hz), 1.56-1.73 (4H, m), 2.29 (2H, t,J=7 Hz), 2.46-2.56 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 5.96(1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.38-7.48 (2H, m), 7.78 (1H, t,J=8 Hz)

MS (ESI⁺): m/z 372 (M+H), MS (ESI⁻): m/z 370

EXAMPLE 1035-[7-Ethyl-4-(3-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.46-1.63 (4H, m), 2.22 (2H, t,J=7 Hz), 2.44-2.53 (2H, m), 2.54 (3H, s), 3.01 (2H, q, J=7 Hz), 3.82(3H, s), 5.92 (1H, d, J=4 Hz), 6.49 (1H, d, J=4 Hz), 6.87-7.01 (3H, m),7.37 (1H, t, J=8 Hz)

MS (ESI⁺): m/z 367, MS (ESI⁻): m/z 365

EXAMPLE 1045-[4-(3,5-Dichlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.42-1.53 (2H, m), 1.53-1.66 (2H,m), 2.27 (2H, t, J=7 Hz), 2.41-2.49 (2H, m), 2.54 (3H, s), 3.01 (2H, q,J=7 Hz), 5.88 (1H, d, J=4 Hz), 6.52 (1H, d, J=4 Hz), 7.26 (2H, m), 7.45(1H, m)

MS (ESI⁺): m/z 405, MS (ESI⁻): m/z 403

EXAMPLE 1055-[4-(5-Chloro-2-thienyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.36 (3H, t, J=7 Hz), 1.48-1.62 (2H, m), 1.62-1.73 (2H,m), 2.34 (2H, t, J=7 Hz), 2.53 (3H, s), 2.58-2.67 (2H, m), 2.99 (2H, q,J=7 Hz), 6.20 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 6.94 (1H, d, J=4Hz), 6.98 (1H, d, J=4 Hz)

MS (ESI⁺): m/z 377, MS (ESI⁻): m/z 375

EXAMPLE 1065-[7-Ethyl-4-(3-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.64 (4H, m), 2.23 (2H, t,J=7 Hz), 2.41-2.49 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=7 Hz), 5.88(1H, d, J=4 Hz), 6.50 (1H, d, J=4 Hz), 7.03-7.16 (3H, m), 7.38-7.47 (1H,m)

MS (ESI⁺): m/z 355, MS (ESI⁻): m/z 353

EXAMPLE 1075-[7-Ethyl-2-methyl-4-(3-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.39 (3H, t, J=7 Hz), 1.47-1.65 (4H, m), 2.20-2.30 (2H,m), 2.45-2.53 (2H, m), 2.59 (3H, s), 3.05 (2H, q, J=7 Hz), 5.87 (1H, d,J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.62 (1H, t, J=8 Hz), 7.79 (1H, t, J=8Hz), 7.87 (1H, d, J=8 Hz), 8.21 (2H, m), 8.88 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 388, MS (ESI⁻): m/z 386

EXAMPLE 1085-[7-Ethyl-2-methyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.70 (4H, m), 2.20-2.30 (2H,m), 2.37-2.53 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=7 Hz), 5.84 (1H, d,J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.39 (2H, d, J=7 Hz), 8.74 (2H, d, J=7Hz)

EXAMPLE 1095-[7-Ethyl-4-(3-methoxy-5-isoxazolyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.36 (3H, t, J=7 Hz), 1.57-1.84 (4H, m), 2.41 (2H, t,J=7 Hz), 2.55 (3H, s), 2.63-2.72 (2H, m), 3.02 (2H, q, J=7 Hz), 4.08(3H, s), 6.27 (1H, s), 6.34 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz)

EXAMPLE 1105-[7-Ethyl-4-(3-methoxyphenyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.06-1.33 (4H, m), 1.36 (3H, t, J=7 Hz), 1.91 (2H, t,J=7 Hz), 2.42-2.53 (2H, m), 3.01 (2H, q, J=7 Hz), 3.83 (3H, s), 6.03(1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 6.93-7.02 (3H, m), 7.36-7.54 (6H,m)

MS (ESI⁺): m/z 429

EXAMPLE 1115-[7-Ethyl-2-methyl-4-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.36 (3H, t, J=7 Hz), 1.52-1.77 (4H, m), 2.35 (2H, t,J=7 Hz), 2.55 (6H, s), 2.56-2.67 (2H, m), 3.01 (2H, q, J=7 Hz), 6.16(1H, d, J=4 Hz), 6.23 (1H, s), 6.54 (1H, d, J=4 Hz)

MS (ESI⁺): m/z 342, MS (ESI⁻): m/z 340

EXAMPLE 1125-[7-Ethyl-2-phenyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.11-1.33 (4H, m), 1.36 (3H, t, J=7 Hz), 1.99 (2H, t,J=7 Hz), 2.38-2.50 (2H, m), 3.03 (2H, q, J=7 Hz), 5.94 (1H, d, J=4 Hz),6.63 (1H, d, J=4 Hz), 7.38-7.56 (7H, m), 8.74 (2H, d, J=6 Hz)

EXAMPLE 1135-[7-Ethyl-2-phenyl-4-(2-pyrazinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.10-1.33 (4H, m), 1.36 (3H, t, J=7 Hz), 1.95 (2H, t,J=7 Hz), 2.45-2.57 (2H, m), 3.02 (2H, q, J=7 Hz), 6.05 (1H, d, J=4 Hz),6.66 (1H, d, J=4 Hz), 7.40-7.55 (5H, m), 8.67 (1H, d, J=3 Hz), 8.77 (1H,s), 8.85 (1H, s)

MS (ESI⁺): m/z 401, MS (ESI⁻): m/z 399

EXAMPLE 1145-[7-Ethyl-2-phenyl-4-(3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.05-1.30 (4H, m), 1.36 (3H, t, J=7 Hz), 1.95 (2H, t,J=7 Hz), 2.35-2.48 (2H, m), 3.02 (2H, q, J=7 Hz), 5.94 (1H, d, J=4 Hz),6.62 (1H, d, J=4 Hz), 7.40-7.55 (6H, m), 7.76-7.83 (1H, m), 8.65-8.72(2H, m)

MS (ESI⁺): m/z 400, MS (ESI⁻): m/z 398

EXAMPLE 1155-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.42-1.64 (4H, m), 2.27 (2H, t,J=7 Hz), 2.48-2.62 (2H, m), 3.04 (2H, q, J=7 Hz), 3.45 (3H, s), 4.62(2H, s), 5.90 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.27 (1H, m), 7.38(1H, s), 8.53 (1H, d, J=5 Hz)

MS (ESI⁺): m/z 402

EXAMPLE 1165-[7-Ethyl-2-(methoxymethyl)-4-(3-methoxyphenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.19 (2H, t,J=7 Hz), 2.55-2.66 (2H, m), 3.03 (2H, q, J=7 Hz), 3.45 (3H, s), 3.82(3H, s), 4.62 (2H, s), 5.96 (1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz),6.87-7.00 (3H, m), 7.37 (1H, t, J=8 Hz)

MS (ESI⁺): m/z 397, MS (ESI⁻): m/z 395

EXAMPLE 1175-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.20-1.50 (4H, m), 1.38 (3H, t, J=7 Hz), 2.15 (2H, t,J=7 Hz), 2.55-2.68 (2H, m), 3.04 (2H, q, J=7 Hz), 5.93 (1H, d, J=4 Hz),6.64 (1H, d, J=4 Hz), 7.13 (1H, t, J=5 Hz), 7.28 (1H, d, J=5 Hz),7.35-7.47 (3H, m), 8.54 (1H, d, J=5 Hz)

MS (ESI⁺): m/z 440

EXAMPLE 1185-[7-Ethyl-2-(methoxymethyl)-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.39 (3H, t, J=7 Hz), 1.45-1.60 (4H, m), 2.16 (2H, m),2.55-2.75 (2H, m), 3.07 (2H, q, J=7 Hz), 3.47 (3H, s), 4.66 (2H, s),5.89 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.45-7.53 (1H, m), 7.72 (1H,d, J=8 Hz), 7.86 (1H, s), 8.22 (2H, m), 8.94 (1H, m)

MS (ESI⁺): m/z 418, MS (ESI⁻): m/z 416

EXAMPLE 1195-[7-Ethyl-2-(methoxymethyl)-4-(3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.38 (3H, t, J=7 Hz), 1.45-1.64 (4H, m), 2.22 (2H, t,J=7 Hz), 2.48-2.68 (2H, m), 3.06 (2H, q, J=7 Hz), 3.46 (3H, s), 4.63(2H, s), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.48 (1H, m), 7.78(1H, m), 8.62 (1H, m), 8.69 (1H, m)

MS (ESI⁺): m/z 368

EXAMPLE 1205-[4-(3-Chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.63 (4H, m), 2.23 (2H, t,J=7 Hz), 2.53-2.63 (2H, m), 3.04 (2H, q, J=7 Hz), 3.45 (3H, s), 4.63(2H, s), 5.93 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.25 (1H, m), 7.36(1H, s), 7.42 (2H, m)

EXAMPLE 1215-[7-Ethyl-2-methyl-4-(3-methylphenyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.23-1.63 (4H, m), 1.37 (3H, t, J=7 Hz), 2.22 (2H, t,J=7 Hz), 2.40 (3H, s), 2.40-2.49 (2H, m), 2.54 (3H, s), 3.02 (2H, q, J=7Hz), 5.89 (1H, d, J=4 Hz), 6.48 (1H, d, J=4 Hz), 7.10-7.14 (2H, m),7.23-7.27 (1H, m), 7.32-7.38 (1H, m)

MS (ESI⁺): m/z 351

EXAMPLE 1245-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.44-1.65 (4H, m), 2.16-2.26 (2H,m), 2.43 (3H, s), 2.47-2.69 (2H, m), 3.03 (2H, q, J=7 Hz), 3.45 (3H, s),4.63 (2H, m), 5.88 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.56 (1H, s),8.42 (1H, s), 8.53 (1H, s)

MS (ESI⁺): m/z 382, MS (ESI⁻): m/z 380

EXAMPLE 1255-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.67 (4H, m), 2.27 (2H, t,J=7 Hz), 2.38-2.52 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 5.87(1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.88 (1H, m), 8.53 (1H, d, J=2Hz), 8.77 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 416, 418

EXAMPLE 1265-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.25 (2H, t,J=7 Hz), 2.49-2.68 (2H, m), 3.03 (2H, q, J=7 Hz), 3.45 (3H, s), 4.63(2H, s), 5.91 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.89 (1H, m), 8.51(1H, s), 8.79 (1H, m)

MS (ESI⁺): m/z 446, 448

EXAMPLE 1275-[4-(5,6-Dichloro-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.43-1.68 (4H, m), 2.29 (2H, t,J=7 Hz), 2.38-2.52 (2H, m), 2.57 (3H, s), 3.02 (2H, q, J=7 Hz), 5.87(1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.81 (1H, d, J=2 Hz), 8.31 (1H,d, J=2 Hz)

MS (ESI⁺): m/z 406, MS (ESI⁻): m/z 404

EXAMPLE 1285-[7-Ethyl-2-methyl-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.68 (4H, m), 2.23 (2H, t,J=7 Hz), 2.38-2.53 (2H, m), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 5.46(1H, d, J=1 Hz), 5.86 (1H, d, J=4 Hz), 5.89 (1H, d, J=17 Hz), 6.52 (1H,d, J=4 Hz), 6.72-6.83 (1H, dd, J=11 Hz, 17 Hz), 7.77 (1H, m), 8.47 (1H,d, J=2 Hz), 8.68 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 364

EXAMPLE 1295-[7-Ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.22 (2H, t,J=7 Hz), 2.45-2.73 (2H, m), 3.04 (2H, q, J=7 Hz), 3.46 (3H, s), 4.63(2H, m), 5.44 (1H, d, J=11 Hz), 5.87 (1H, d, J=18 Hz), 5.92 (1H, d, J=4Hz), 6.57 (1H, d, J=4 Hz), 6.72-6.83 (1H, dd, J=11 Hz, 18 Hz), 7.78 (1H,s), 8.48 (1H, s), 8.68 (1H, s)

MS (ESI⁺): m/z 394 (M+H), MS (ESI⁻): m/z 392

EXAMPLE 1305-[4-(5-Acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.38 (3H, t, J=7 Hz), 1.44-1.60 (4H, m), 2.22 (2H, t,J=7 Hz), 2.50-2.63 (2H, m), 2.69 (3H, s), 3.02 (2H, q, J=7 Hz), 3.46(3H, s), 4.64 (2H, s), 5.86 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 8.29(1H, m), 8.79 (1H, d, J=2 Hz), 9.23 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 410, MS (ESI⁻): m/z 408

EXAMPLE 1314-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

NMR (CDCl₃, δ): 1.38 (3H, t, J=7 Hz), 1.70-1.87 (2H, m), 2.26 (2H, t,J=7 Hz), 2.45 (3H, s), 2.53-2.81 (2H, m), 3.06 (2H, q, J=7 Hz), 3.46(3H, s), 4.66 (2H, m), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.61(1H, s), 8.43 (1H, s), 8.46 (1H, s)

MS (ESI⁺): m/z 368

EXAMPLE 1323-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 2.30-2.60 (2H, m), 2.42 (3H, s),2.77-3.13 (2H, m), 3.05 (2H, q, J=7 Hz), 3.47 (3H, s), 4.66 (2H, s),5.91 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.58 (1H, s), 8.42 (1H, s),8.54 (1H, s)

MS (ESI⁺): m/z 354

EXAMPLE 1334-[7-Ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.70-1.88 (2H, m), 2.22-2.32 (2H,m), 2.45 (3H, s), 2.50-2.62 (2H, m), 2.59 (3H, s), 3.02 (2H, q, J=7 Hz),5.86 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.60 (1H, s), 8.42 (2H, m)

MS (ESI⁺): m/z 338, MS (ESI⁻): m/z 336

EXAMPLE 1343-[7-Ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 2.42 (3H, s), 2.40-2.53 (2H, m),2.59 (3H, s), 2.82 (2H, t, J=7 Hz), 3.03 (2H, q, J=7 Hz), 5.86 (1H, d,J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.57 (1H, s), 8.38 (1H, s), 8.52 (1H, s)

MS (ESI⁺): m/z 324, MS (ESI⁻): m/z 322

EXAMPLE 1353-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

mp: 181-182° C.

NMR (CDCl₃, δ): 1.38(2H, t, J=7 Hz), 2.4(2H, t, J=7 Hz), 2.58(3H, s),2.74-2.85(2H, m), 3.01(2H, q, J=7 Hz), 5.89(1H, d, J=4 Hz), 6.55(1H, d,J=4 Hz), 7.87(1H, s), 8.54(1H, s), 8.77(1H, s)

MS: (m/z) 388 (M⁺), 390(M⁺+2), 114(bp)

EXAMPLE 1365-[4-(3-Cyanophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NNMR (CDCl₃, δ): 1.30-1.57 (5H, m), 2.21 (2H, t, J=8 Hz), 2.47-2.57 (2H,m), 3.03 (2H, q, J=8 Hz), 3.45 (3H, s), 4.62 (2H, s), 5.84 (1H, d, J=5Hz), 6.57 (1H, d, J=5 Hz), 7.59-7.64 (2H, m), 7.68 (1H, br s), 7.75 (1H,m)

MS (ESI⁺): 392 (M+H)

EXAMPLE 136-25-[4-[3-(Aminocarbonyl)phenyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.30-1.70 (5H, overlappoed with H₂O), 2.20-2.50 (4H, m),2.80-2.93 (2H, m), 3.03 (2H, q, J=8 Hz), 3.46 (3H, s), 4.54 (1H, d, J=10Hz), 4.77 (1H, d, J=10 Hz), 5.80 (1H, d, J=5 Hz), 6.55 (1H, d, J=5 Hz),7.43-7.50 (2H, m), 7.58 (1H, t, J=8 Hz), 7.77 (1H, br s), 7.88 (1H, brs), 7.99 (1H, br d, J=8 Hz)

MS (ESI⁺): 410 (M+H)

EXAMPLE 1375-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.06-1.26 (4H, m), 1.36 (3H, t, J=7 Hz), 1.94 (2H, t,J=7 Hz), 2.40 (2H, m), 2.99 (2H, q, J=7 Hz), 5.96 (1H, d, J=5 Hz), 6.63(1H, d, J=5 Hz), 7.40-7.52 (5H, m), 7.93 (1H, s), 8.59 (1H, s), 8.77(1H, s)

EXAMPLE 1385-[7-Ethyl-4-(5-ethyl-3-pyridinyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.05-1.42 (10H, m), 1.92 (2H, m), 2.41 (2H, m), 2.75(2H, q, J=7 Hz), 3.01 (2H, q, J=7 Hz), 5.93 (1H, d, J=5 Hz), 6.55 (1H,d, J=5 Hz), 7.37-7.54 (5H, m), 7.62 (1H, m), 8.45 (1H, m), 8.52 (1H, m)

EXAMPLE 1395-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.25-1.48 (7H, m), 2.12 (2H, t, J=7 Hz), 2.62 (2H, m),3.03 (2H, q, J=7 Hz), 5.93 (1H, d, J=5 Hz), 6.64 (1H, d, J=5 Hz), 7.14(1H, m), 7.37 (1H, d, J=5 Hz), 7.43 (1H, d, J=5 Hz), 7.92 (1H, s) 8.58(1H, m), 8.79 (1H, m)

MS (ESI⁺): m/z 484 (M+H)

EXAMPLE 1405-[2-[(Benzyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.34-1.48 (5H, m), 2.09 (2H, m),2.53 (2H, m), 3.04 (2H, q, J=7 Hz), 4.07 (2H, J=7 Hz), 4.65 (2H, s),4.72 (2H, s), 5.90 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.29-7.38 (5H,m), 7.86 (1H, s), 8.54 (1H, m), 8.77 (1H, m)

EXAMPLE 1415-(4-(5-Bromo-3-pyridinyl)-2-{[(4-cyanobenzyl)oxy]methyl}-7-ethylpyrrolo[1,2-b]pyridazin-3-yl)pentanoicacid

NMR (CDCl₃, δ): 1.35-1.56 (7H, m), 2.18 (2H, m), 2.57 (2H, m), 3.03 (2H,q, J=7 Hz), 4.69 (2H, s), 4.74 (2H, s), 5.92 (1H, d, J=5 Hz), 6.62 (1H,d, J=5 Hz), 7.47 (2H, d, J=8 Hz), 7.64 (2H, d, J=8 Hz), 7.88 (1H, s),8.54 (1H, m), 8.79 (1H, m)

EXAMPLE 1425-[2-[(Benzylamino)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.20-1.49 (7H, m), 2.17 (2H, m), 2.32 (2H, m), 3.04 (2H,q, J=7 Hz), 4.29 (4H, s), 5.94 (1H, d, J=5 Hz), 6.51 (1H, s, br), 6.12(1H, d, J=5 Hz), 7.27-7.36 (3H, m), 7.48 (2H, m), 7.84 (1H, m), 8.49(1H, m), 8.75 (1H, m)

EXAMPLE 1435-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.20-1.38 (5H, m), 1.49 (4H, m), 2.24 (2H, q, J=7 Hz),2.59 (4H, m), 3.01 (2H, q, J=7 Hz), 3.70 (4H, m), 5.88 (1H, d, J=5 Hz),6.55 (1H, d, J=5 Hz), 7.90 (1H, m), 8.55 81H, m), 8.78 (1H, m)

EXAMPLE 1445-{4-[5-(Aminocarbonyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid from ethyl5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]-pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.10-1.70 (4H, m), 1.37 (3H, t, J=7 Hz), 2.24-2.77 (4H,m), 2.59 (3H, s), 3.02 (2H, q, J=7 Hz), 5.77 (1H, d, J=4 Hz), 6.52 (1H,d, J=4 Hz), 7.57 (1H, br), 7.97 (1H, br), 8.07 (1H, s), 8.68 (1H, s),9.18 (1H, s)

MS (ESI⁺): m/z 381

EXAMPLE 1455-[4-[5-(Aminocarbonyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.16-1.72 (4H, m), 1.37 (3H, t, J=7 Hz), 2.25-2.50 (3H,m), 2.83-2.97 (1H, m), 3.04 (2H, q, J=7 Hz), 3.47 (3H, s), 4.56 (1H, d,J=17 Hz), 4.77 (1H, d, J=17 Hz), 5.81 (1H, d, J=4 Hz), 6.58 (1H, d, J=4Hz), 7.52 (1H, br), 7.82 (1H, br), 8.11 (1H, m), 8.70 (1H, d, J=2 Hz),9.18 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 411

EXAMPLE 146

To a solution of triethyl 4-phosphonocrotonate (2.13 g) intetrahydrofuran (20 mL) was added dropwise lithiumbis(trimethylsilyl)amide (1.1 mol/L solution in hexanes, 15 mL) at 2° C.under nitrogen, and the mixture was stirred at the same temperature for30 minutes. To the mixture was added dropwise a solution of4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde(1.2 g) in tetrahydrofuran (20 mL). After being stirred for 3 hours at2° C., the mixture was poured into saturated aqueous ammonium chloride,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water, brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (eluent; 3% ethyl acetate in n-hexane) to give the titlecompound (1.06 g) as an yellow crystals.

Ethyl(2E,4E)-5-[4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4-pentadienoate

NMR (300 MHz, CDCl₃, δ): 1.28(3H, t, J=7 Hz), 1.35(6H, d, J=7 Hz),3.30(1H, quintet, J=7 Hz), 4.19(2H, quartet, J=7 Hz), 5.63(1H, d, J=16Hz), 5.94(1H, dd, J=16, 11 Hz), 6.16(1H, dd, J=4.4, 1.5 Hz), 6.76(1H,dd, J=4.4, 2.6 Hz), 6.78(1H, d, J=16 Hz), 7.11-7.23(3H, m),7.33-7.40(2H, m), 7.72(1H, dd, J=2.6, 1.5 Hz)

MS (ESI⁺): m/z 379 (M+H)

The following compounds were obtained in substantially the same manneras that of Example 146.

EXAMPLE 147 Ethyl(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenoate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 1.40 (6H, d, J=7 Hz), 3.38 (1H,m), 4.16 (2H, q, J=7 Hz), 5.57 (1H, d, J=15 Hz), 6.25 (1H, d, J=5 Hz),6.74 (1H, d, J=5 Hz), 7.15 (1H, d, J=8.5 Hz), 7.29 (1H, d, J=85 Hz),7.33 (1H, d, J=8.5 Hz), 7.35 (1H, d, J=85 Hz), 7.63 (1H, d, J=15 Hz)

MS (ESI⁻): m/z 385 (M−H)

EXAMPLE 148(2E)-3-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenenitrile

NMR (CDCl₃, δ): 1.41 (6H, d, J=7 Hz), 3.28 (1H, m), 4.99 (1H, d, J=15Hz), 6.24 (1H, d, J=5 Hz), 6.76 (1H, d, J=15 Hz), 7.17-7.27 (2H, m),7.30-7.40 (3H, m)

MS (ESI⁻): m/z 340 (M+H)

EXAMPLE 149

To a solution of ethyl(2E,4E)-5-[4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4-pentadienoate(300 mg) in tetrahydrofuran (3 mL) and acetic acid (1 mL) was addeddropwise N-chlorosuccinimide (106 mg). The mixture was stirred atambient temperature for 24 hours. The resulting mixture was concentratedand partitioned between saturated aqueous sodium hydrogencarbonate andethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate, and concentrated. The residue was purifiedby silica gel column chromatography (eluent; 1% ethyl acetate inn-hexane) to give the title compound (110 mg) as an oil.

Ethyl(2E,4E)-5-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4-pentadienoate

NMR (300 MHz, CDCl₃, δ): 1.28(3H, t, J=7 Hz), 1.40(6H, d, J=7 Hz),3.33(1H, quintet, J=7 Hz), 4.19(2H, quartet, J=7 Hz), 5.64(1H, d, J=16Hz), 5.94(1H, dd, J=16, 11 Hz), 6.18(1H, d, J=4.4 Hz), 6.71(1H, d, J=4.4Hz), 6.79(1H, d, J=16 Hz), 7.13-7.23(3H, m), 7.32-7.37(2H, m)

The following compounds were obtained in substantially the same manneras that of Example 149.

EXAMPLE 151 Ethyl7-chloro-4-(2-chlorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (300 MHz, CDCl₃, δ): 0.89 (3H, t, J=75 Hz), 1.41 (6H, d, J=75 Hz),3.41-3.56 (1H, m), 4.00 (2H, q, J=7.5 Hz), 6.16 (1H, d, J=5 Hz), 6.76(1H, d, J=5 Hz), 7.25-7.53 (4H, m)

MS (ES+): m/e 377.44

EXAMPLE 152 Ethyl7-chloro-2-isopropyl-4-(2-naphthyl)pyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (300 MHz, CDCl₃, δ): 0.78 (3H, t, J=75 Hz), 1.43 (6H, d, J=75 Hz),3.29-3.41 (1H, m), 3.95 (2H, q, J=75 Hz), 6.40 (1H, d, J=5 Hz), 6.79(1H, d, J=5 Hz), 7.50-7.60 (3H, m), 7.81-8.00 (4H, m)

EXAMPLE 153

To a solution of ethyl(2E,4E)-5-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4-pentadienoate(82 mg) in ethanol (2 mL) was added 1N sodium hydroxide solution (0.5mL), and the mixture was stirred at ambient temperature for 12 hours.The resulting mixture was concentrated in vacuo, and the residue wasdissolved in water, acidified with 1N hydrochloric acid, and extractedwith ethyl acetate. The organic layer was washed with water, brine,dried over anhydrous magnesium sulfate and concentrated. The residue waspurified by silica gel column chromatography (eluent; 50% ethyl acetatein n-hexane) to give the title compound (14 mg) as a brown amorphoussolid, which was recrystallized from aqueous ethanol.

(2E,4E)-5-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2,4-pentadienoicacid

NMR (300 MHz, CDCl₃, δ): 1.40 (6H, d, J=7 Hz), 1.30-1.90 (1H, br), 3.34(1H, quintet, J=7 Hz), 5.64 (1H, d, J=16 Hz), 5.98 (1H, dd, J=16, 11Hz), 6.19 (1H, d, J=4.4 Hz), 6.72 (1H, d, J=4.4 Hz), 6.84 (1H, d, J=16Hz), 7.14-7.37 (5H, m)

MS (ESI⁻): m/z 383 (M−H)

EXAMPLE 154

To a mixture of ethyl5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(130 mg) in toluene (5 mL) was added 28% sodium methylate metanolsolution (536 mg) and the mixture was heated under reflux for 2 hours.The solution was acidified to pH 4 with 1N hydrochloric acid andextracted with chloroform. The organic layer was separated, dried overmagnesium sulfate, and evaporated in vacuo. To the residue in ethanol (5mL) was added 1N sodium hydroxide solution (1 mL) and the mixture washeated at 60° C. for 1 hour. The solution was acidified to pH 4 with 1Nhydrochloric acid and extracted with chloroform. The organic layer wasseparated, washed with brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by silica gel columnchromatography eluting with a mixture of hexane and ethyl acetate (1:1)to give5-[7-ethyl-4-(2-methoxy-4-pyridinyl)-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid as an yellow powder (50.0 mg).

5-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.30-1.48 (4H, m), 1.38 (3H, t, J=7 Hz), 2.13 (2H, t,J=7 Hz), 2.58-2.69 (2H, m), 3.02 (2H, q, J=7 Hz), 4.02 (3H, s), 5.96(1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 6.78 (1H, s), 6.90 (1H, d, J=5Hz), 7.12 (1H, m), 7.34 (1H, m), 7.42 (1H, d, J=5 Hz), 8.29 (1H, d, J=5Hz)

The following compounds were obtained in substantially the same manneras that of Example 154.

EXAMPLE 1555-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.31-1.64 (7H, m), 2.25 (2H, t, J=8 Hz), 2.43 (2H, br t,J=8 Hz), 2.54 (3H, s), 3.00 (2H, q, J=8 Hz), 4.04 (3H, s), 5.60 (1H, brs), 5.90 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 6.81 (1H, br s), 6.93(1H, br d, J=7 Hz), 8.30 (1H, d, J=7 Hz)

MS (ESI⁺): m/z 368 (M+H)

EXAMPLE 155-25-[7-Ethyl-2-methyl-4-(2-oxo-1,2-dihydro-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.29-1.67 (7H, m), 2.29 (2H, t, J=8 Hz), 2.35-2.60 (5H,m), 3.00 (2H, q, J=8 Hz), 5.94 (1H, d, J=5 Hz), 6.54 (1H, d, J=5 Hz),6.64 (1H, br d, J=7 Hz), 6.84 (1H, br s), 7.70 (1H, br d, J=7 Hz)

MS (ESI⁺): m/z 354 (M+H)

The following compounds were obtained in substantially the same manneras that of Example 154.

EXAMPLE 1565-[7-Ethyl-4-(2-methoxy-4-pyridinyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.08-1.30 (4H, m), 1.36 (3H, t, J=7 Hz), 1.95 (2H, t,J=7 Hz), 2.48-2.53 (2H, m), 3.03 (2H, q, J=7 Hz), 4.01 (3H, s), 6.02(1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 6.82 (1H, s), 6.94 (1H, d, J=5Hz), 7.42-7.54 (5H, m), 8.29 (1H, d, J=5 Hz)

MS (ESI⁺): m/z 430

EXAMPLE 1575-[7-Ethyl-2-(methoxymethyl)-4-(2-methoxy-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.64 (4H, m), 2.24 (2H, t,J=7 Hz), 2.53-2.64 (2H, m), 3.03 (2H, q, J=7 Hz), 3.45 (3H, s), 4.01(3H, s), 4.61 (2H, s), 5.94 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 6.77(1H, s), 6.89 (1H, d, J=5 Hz), 8.28 (1H, d, J=5 Hz)

MS (ESI⁺): m/z 398, MS (ESI⁻): m/z 396

EXAMPLE 158

To a solution of ethyl5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate(120 mg) in toluene (5 mL) and tetrahydrofuran (10 mL) was added sodiumthiomethoxide (91.0 mg) and the mixture was heated under reflux for 4hours. The solution was acidfied with 1N hydrochloric acid and extractedwith chloroform. The organic layer was separated, washed with brine,dried over magnesium sulfate, and evaporated in vacuo. The residue waspurified by silica gel column chromatography eluting with a mixture ofhexane and ethyl acetate (10:1-3:1) to give5-{7-ethyl-4-[2-(methylthio)-4-pyridinyl]-2-phenylpyrrolo-[1,2-b]pyridazin-3-yl}pentanoicacid as an yellow powder (85.0 mg).

5-{7-Ethyl-4-[2-(methylthio)-4-pyridinyl]-2-phenylpyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

NMR (CDCl₃, δ): 1.07-1.17 (2H, m), 1.17-1.30 (2H, m), 1.36 (3H, t, J=7Hz), 1.97 (2H, t, J=7 Hz), 2.38-2.48 (2H, m), 2.61 (3H, s), 3.02 (2H, q,J=7 Hz), 5.98 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.03 (1H, dd, J=1Hz, 5 Hz), 7.25 (1H, m), 7.43-7.55 (5H, m), 8.57 (1H, d, J=5 Hz)

MS (ESI⁺): m/z 446 (M+H)

EXAMPLE 159

A mixture of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile(3.00 g), ethyl 6-benzoylhexanoate (5.07 g), andtrifluoromethanesulfonic acid (376 mg) in toluene (60 mL) was refluxedfor 1 hour and 20 minutes with Dean-Stark equipment. The mixture waspartitioned between ethyl acetate (60 mL) and water (60 mL), and theorganic layer was washed with saturated sodium bicarbonate (60 mL) andbrine (60 mL), dried over magnesium sulfate, and evaporated to give adark colored oil. Flash silica gel column chromatography eluting withacetone=1-100 to 7-100 afforded ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo-[1,2-b]pyridazin-3-yl]pentanoateas an orange oil (4.45 g, 78.6%).

Ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.01-1.27 (7H, m), 1.36 (3H, t, J=7 Hz), 1.86 (2H, t,J=7 Hz), 2.40 (2H, m), 3.02 (2H, q, J=7 Hz), 4.02 (2H, q, J=7 Hz), 5.90(1H, d, J=5 Hz), 6.61 (1H, d, J=5 Hz), 7.44-7.53 (5H, s), 7.60-7.69 (2H,m), 7.74-7.79 (2H, m)

The following compound was obtained in substantially the same manner asthat of Example 159.

EXAMPLE 160 Ethyl5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.21 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.25-1.48(4H, m), 2.07 (2H, t, J=7 Hz), 2.57-2.68 (2H, m), 3.04 (2H, q, J=7 Hz),4.12 (2H, q, J=7 Hz), 5.93 (1H, d, J=4 Hz), 6.64 (1H, d, J=4 Hz), 7.12(1H, m), 7.28 (1H, dd, J=1 Hz, 5 Hz), 7.37 (1H, m), 7.41 (1H, s), 7.45(1H, d, J=5 Hz), 8.55 (1H, d, J=5 Hz)

MS: (m/z) 468 (M+H)

EXAMPLE 161 Ethyl5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.05-1.17 (2H, m), 1.19-1.30 (2H, m), 1.28 (3H, t, J=7Hz), 1.36 (3H, t, J=7 Hz), 1.91 (2H, t, J=7 Hz), 2.38-2.48 (2H, m), 3.02(2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.96 (1H, d, J=4 Hz), 6.64 (1H,d, J=4 Hz), 7.31 (1H, dd, J=2 Hz, 5 Hz), 7.41-7.54 (6H, m), 8.56 (1H, d,J=5 Hz)

MS (ESI⁺): m/z 462 (M+H)

EXAMPLE 162 Ethyl[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]acetate

NMR (CDCl₃, δ): 1.08 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 3.03 (2H, q,J=7 Hz), 3.36 (2H, s), 3.93 (2H, q, J=7 Hz), 6.09 (1H, d, J=5 Hz), 6.66(1H, d, J=5 Hz), 7.33 (1H, m), 7.41-7.50 (8H, m)

MS (ESI⁺): m/z 419 (M+H)

EXAMPLE 163 Ethyl4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (CDCl₃, δ): 1.06 (3H, t, J=7 Hz), 1.41 (3H, t, J=7 Hz), 3.08 (2H, q,J=7 Hz), 4.09 (2H, q, J=7 Hz), 6.34 (1H, d, J=5 Hz), 6.53 (1H, m), 6.74(1H, d, J=5 Hz), 6.97 (1H, m), 7.39-7.46 (3H, m), 7.52 (2H, m)

MS (ESI⁺): m/z 395 (M+H)

EXAMPLE 164 Ethyl4-(3-chlorophenyl)-7-ethyl-2-(2-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (CDCl₃, δ): 0.94 (3H, m), 1.41 (3H, m), 3.08 (2H, q, J=7 Hz), 3.11(2H, m), 4.00 (2H, m), 6.36 (1H, m), 6.76 (1H, m), 7.26-7.55 (4H, m),7.84 (1H, m), 8.15 (1H, m), 8.57 (1H, m)

MS (ESI⁺): m/z 406 (M+H)

EXAMPLE 165 Ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-(1,3-thiazol-2-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.21 (3H, t, J=7 Hz), 1.33-1.50 (7H, m), 2.14 (2H, t,J=7 Hz), 2.46 (2H, m), 2.97 (2H, q, J=7 Hz), 3.06 (2H, q, J=7 Hz), 4.05(2H, q, J=7 Hz), 5.88 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.43 (1H,d, J=3 Hz), 7.64-7.67 (2H, m), 7.70 (1H, m), 7.78 (1H, m), 7.93 (1H, d,J=3 Hz)

EXAMPLE 166 Methyl5-[4-(3-cyanophenyl)-7-ethyl-2-(1-methyl-1H-pyrrol-2-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.04 (2H, m), 1.21-1.41 (5H, m), 1.99 (2H, t, J=7 Hz),2.46 (2H, m), 3.02 (2H, q, J=7 Hz), 3.60 (3H, s), 3.68 (3H, s), 5.89(1H, d, J=5 Hz), 6.23 (1H, m), 6.35 (1H, m), 6.62 (1H, d, J=5 Hz), 6.76(1H, m), 7.62-7.79 (4H, m)

EXAMPLE 167 Ethyl3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoate

NMR (CDCl₃, δ): 1.08 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.02 (2H,m), 2.80 (2H, m), 3.02 (2H, q, J=7 Hz), 3.89 (2H, q, J=7 Hz), 6.01 (1H,d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.31 (1H, m), 7.41-7.54 (8H, m)

EXAMPLE 168 Ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.17-1.49 (10H, m), 2.08 (2H, t, J=7 Hz), 2.57 (2H, m),3.03 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.91 (1H, d, J=5 Hz), 6.66(1H, d J=5 Hz), 7.55 (1H, s), 7.62-7.68 (3H, m), 7.78 (1H, m), 8.04 (1H,s)

EXAMPLE 169 Ethyl5-[7-ethyl-4-(3-methoxyphenyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.05-1.29 (4H, m), 1.18 (3H, t, J=7 Hz), 1.36 (3H, t,J=7 Hz), 1.86 (2H, t, J=7 Hz), 2.42-2.52 (2H, m), 3.02 (2H, q, J=7 Hz),3.84 (3H, s), 4.02 (2H, q, J=7 Hz), 6.02 (1H, d, J=4 Hz), 6.60 (1H, d,J=4 Hz), 6.95-7.02 (3H, m), 7.36-7.56 (6H, m)

EXAMPLE 170 Ethyl5-[7-ethyl-2-phenyl-4-(4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.04-1.29 (4H, m), 1.19 (3H, t, J=7 Hz), 1.36 (3H, t,J=7 Hz), 1.88 (2H, t, J=7 Hz), 2.38-2.48 (2H, m), 3.02 (2H, q, J=7 Hz),4.04 (2H, q, J=7 Hz), 5.95 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.36(2H, m), 7.42-7.54 (5H, m), 8.76 (2H, m)

EXAMPLE 171 Ethyl5-[7-ethyl-2-phenyl-4-(2-pyrazinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.10-1.32 (4H, m), 1.18 (3H, t, J=7 Hz), 1.36 (3H, t,J=7 Hz), 1.90 (2H, t, J=7 Hz), 2.45-2.55 (2H, m), 3.02 (2H, q, J=7 Hz),4.02 (2H, q, J=7 Hz), 6.05 (1H, d, J=4 Hz), 6.66 (1H, d, J=4 Hz),7.43-7.56 (5H, m), 8.66 (1H, m), 8.77 (1H, m), 8.86 (1H, m)

EXAMPLE 172 Ethyl5-[7-ethyl-2-phenyl-4-(3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.04-1.30 (4H, m), 1.18 (3H, t, J=7 Hz), 1.37 (3H, t,J=7 Hz), 1.87 (2H, t, J=7 Hz), 2.38-2.50 (2H, m), 3.02 (2H, q, J=7 Hz),4.01 (2H, q, J=7 Hz), 5.96 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz),7.42-7.55 (6H, m), 7.77 (1H, m), 8.66-8.73 (2H, m)

EXAMPLE 173 Ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.12-1.28 (7H, m), 1.36 (3H, t, J=7 Hz), 1.89 (2H, t,J=7 Hz), 2.43 (2H, m), 3.01 (2H, m), 4.02 (2H, q, J=7 Hz), 5.97 (1H, d,J=5 Hz), 6.65 (1H, d, J=5 Hz), 7.43-7.55 (5H, m), 7.93 (1H, m), 8.61(1H, m), 8.79 (1H, m)

EXAMPLE 174 Ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.16-1.46 (10H, m), 1.57 (2H, t, J=7 Hz), 2.62 (2H, m),2.30 (2H, m), 3.03 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.93 (1H, d,J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.36 (1H, m), 7.44 (1H, m), 7.91 (1 H, m)

EXAMPLE 175

To a solution of ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate(1.00 g) in dimethylsulfoxide (20 mL) was added 1N sodium hydroxide(5.31 mL) over 1.5 hours. The reaction was quenched by adding 1Nhydrochloric acid (6 mL) under an ice-bath. The mixture was partitionedbetween ethyl acetate (50 mL) and water (50 mL). The organic layer waswashed with water (50×2 mL) and brine, dried over magnesium sulfate, andevaporated. Flash silica gel column chromatography eluting with ethylacetate-hexane=1/3 to 1/1 afforded5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid as an yellow solid (668 mg).

5-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.03-1.25 (4H, m), 1.36 (3H, t, J=7 Hz), 1.93 (2H, t,J=7 Hz), 2.39 (2H, m), 3.02 (2H, q, J=7 Hz), 5.91(1H, d, J=5 Hz), 6.63(1H, d, J=5 Hz), 7.26-7.53 (5H, s), 7.56-7.69 (2H, m), 7.72-7.79 (2H, m)

MS (ESI⁺): m/z 424 (M+H)

The following compounds were obtained in substantially the same manneras that of Example 175.

EXAMPLE 1765-[4-(3-Cyanophenyl)-7-ethyl-2-(1,3-thiazol-2-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.20-1.52 (7H, m), 2.19 (2H, m), 2.98 (2H, m), 3.04 (2H,q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.38 (1H, d, J=5 Hz), 6.67 (1H, d, J=5Hz), 7.43 (1H, d, J=3 Hz), 7.60-7.64 (2H, m), 7.67 (1H, m), 7.76 (1H,m), 7.92 (1H, d, J=3 Hz)

MS (ESI⁺): m/z 431 (M+H)

EXAMPLE 1775-[4-(3-Cyanophenyl)-7-ethyl-2-(1-methyl-1H-pyrrol-2-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.12 (2H, m), 1.23-1.41 (5H, m), 2.04 (2H, t, J=7 Hz),2.48 (2H, m), 3.02 (2H, q, J=7 Hz), 3.68(3H, s), 5.90 (1H, d, J=5 Hz),6.22 (1H, m), 6.35 (1H, m), 6.62 (1H, d, J=5 Hz), 6.75 (1H, m),7.57-7.789 (4H, m)

MS (ESI⁺) m/z 427 (M+H)

EXAMPLE 1785-[4-(3-Cyanophenyl)-7-ethyl-2-(1,3-oxazol-5-yl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.31-1.49 (7H, m), 2.17 (2H, t, J=7 Hz), 2.57 (2H, m),3.04 (2H, q, J=7 Hz), 5.42 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.56(1H, s), 7.64 (2H, m), 7.67 (1H, s), 7.78 (1H, m), 8.07 (1H, s)

EXAMPLE 1795-[4-(3-Cyanophenyl)-2-(3,5-dimethyl-4-isoxazolyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.04-1.30 (7H, m), 1.97 (2H, t, J=7 Hz), 2.26-2.35 (5H,m), 2.41 (3H, s), 3.00 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.97 (1H,d, J=5 Hz), 6.68 (1H, d, J=5 Hz), 7.61-7.68 (2H, m), 7.73 (1H, s), 7.79(1H, m)

EXAMPLE 180

A solution of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile(120 mg), 1-tert-butyl 7-ethyl2-[(3,5-dimethyl-4-isoxazolyl)carbonyl]heptanedioate (203 mg), andtoluenesulfonic acid monohydrate (3.76 mg) in toluene (1 mL) wasrefluxed for 1 hour.

Additional p-toluenesulfonic acid monohydrate (14.5 mg) was added, andthe mixture was refluxed for 1 hour. The mixture was stirred further for0.5 hour after adding trifluoromethanesulfonic acid (3.76 mg). Themixture was partitioned between ethyl acetate (20 mL) and saturatedsodium bicarbonate (10 mL). The organic layer was washed with brine,dried over magnesium sulfate, and evaporated. Flash silica gel columnchromatography eluting with ethyl acetate-hexane=1/40 to 2/5 affordedethyl5-[4-(3-cyanophenyl)-2-(3,5-dimethyl-4-isoxazolyl)-7-ethylpyrrolo-[1,2-b]pyridazin-3-yl]pentanoateas an yellow gum (75.7 mg, 19.1%).

Ethyl5-[4-(3-cyanophenyl)-2-(3,5-dimethyl-4-isoxazolyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.04-1.30 (7H, m), 1.97 (2H, t, J=7 Hz), 2.26-2.35 (5H,m), 2.41 (3H, s), 3.00 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.97 (1H,d, J=5 Hz), 6.68 (1H, d, J=5 Hz), 7.61-7.68 (2H, m), 7.73 (1H, s), 7.79(1H, m)

EXAMPLE 181

To a solution ofN-[2-(3-cyanobenzoyl)-5-ethyl-1H-pyrrol-1-yl]-2-(methylsulfonyl)acetamide(2.70 g) in tetrahydrofuran (30 mL) was added sodium hydride (601 mg,60% in oil) under an ice-bath. After stirring for 40 minutes, thereaction was quenched by adding 1N hydrochloric acid (15 mL). Themixture was extracted with ethyl acetate (50 mL), and the extract waswashed with water (50×2 mL) and brine (50 mL), dried over magnesiumsulfate, and evaporated to give a brownish yellow solid (3.36 g). Thesolid was triturated in diisopropyl ether (20 mL) to give3-[7-ethyl-3-(methylsulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzonitrileas an yellow powder (2.31 g, 90.1%).

3-[7-Ethyl-3-(methylsulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 2.46-3.07 (5H, m), 6.81 (1H, d,J=5 Hz), 6.70 (1H, d, J=5 Hz), 7.60-7.69 (3H, m), 7.83 (1H, d, J=9 Hz)

The following compound was obtained in substantially the same manner asthat of Example 181.

EXAMPLE 182 Ethyl4-(4-cyanophenyl)-7-ethyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (CDCl₃, δ): 0.78 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 3.02 (2H, q,J=7 Hz), 4.02 (2H, q, J=7 Hz), 6.15 (1H, d, J=5 Hz), 6.64 (1H, d, J=5Hz), 7.42 (2H, d, J=9 Hz), 7.77 (2H, d, J=9 Hz), 11.74 (1H, s, br)

MS (ESI⁺): m/z 336 (M+H)

EXAMPLE 183

To a solution of3-[7-ethyl-3-(methylsulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzonitrile(1.30 g) and triethylamine (578 mg) in dichloromethane (18 mL) was addedtrifluoromethanesulfonic anhydride (1.61 g) under an ice-bath over 30minutes (3 to 7° C.). After stirring for 0.5 hour, the reaction wasquenched by adding water (100 mL). The mixture was partitioned betweenethyl acetate (200 mL) containing chloroform (200 mL) and 1Nhydrochloric acid (50 mL). An insoluble yellow solid was collected byfiltration (0.542 g). The organic layer was washed with brine, driedover magnesium sulfate, and evaporated to give a dark yellow solid (1.27g). Both the solid was combined, and triturated in diisopropyl ether (30mL) to give4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yltrifluoromethanesulfonate as a brownish yellow powder (1.67 g, 92.6%).

4-(3-Cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yltrifluoromethanesulfonate

NMR (CDCl₃, δ): 139 (3H, t, J=7 Hz), 3.02 (2H, q, J=7 Hz), 3.22 (3H, s),6.40 (1H, d, J=5 Hz), 6.93 (1H, d, J=5 Hz), 7.63 (3H, m), 7.82 (1H, m)

EXAMPLE 184

A mixture of4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yltrifluoromethanesulfonate (150 mg) and pyrrolidine (45.6 mg) intetrahydrofuran (1 mL) was refluxed for 1.5 hours. The mixture waspartitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10mL). The organic extract was washed with brine, dried over magnesiumsulfate, and evaporated to give a dark colored solid. Flash silica gelcolumn chromatography eluting with ethyl acetate-hexane=1-4 to 1-2afforded3-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrileas an yellow oil, which was crystalyzed upon standing (112 mg, 89.6%).

3-[7-Ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.38 (3H, t, J=7 Hz), 1.99 (4H, m), 3.99 (2H, q, J=7Hz), 3.22 (3H, s), 3.42-3.70 (4H, m), 6.28 (1H, d, J=5 Hz), 6.68 (1H, d,J=5 Hz), 7.57 (1H, t, J=9 Hz), 7.69-7.78 (3H, m)

MS (ESI⁺): m/z 395 (M+H)

The following compounds were obtained in substantially the same manneras that of Example 184.

EXAMPLE 185 3-[2-(Dimethylamino)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.39 (3H, t, J=7 Hz), 2.97 (6H, s), 3.02 (2H, q, J=7Hz), 3.26 (3H, s), 6.28 (1H, d, J=5 Hz), 6.69 (1H, d, J=5 Hz), 7.57 (1H,t, J=9 Hz), 7.66-7.79 (3H, m)

MS (ESI⁺): m/z 369 (M+H)

EXAMPLE 1863-[7-Ethyl-2-[(2-methoxyethyl)amino]-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.35 (3H, t, J=7 Hz), 2.96 (2H, q, J=7 Hz), 3.07 (3H,s), 3.43 (3H, s), 3.61-3.73 (4H, m), 5.96 (1H, d, J=5 Hz), 6.51 (1H, d,J=5 Hz), 6.75 (1H, m, br), 7.51-7.60 (3H, m), 7.74 (1H, m)

MS (ESI⁺): m/z 399 (M+H)

EXAMPLE 187

A mixture of ethyl 2-(4-fluorobenzoyl)-3-oxo-4-phenylbutanoate (1.4 g),1H-pyrrol-1-amine (350 mg), and p-toluenesulfonic acid monohydrate (41mg) in ethanol (10 ml) was refluxed for 5 hours. The mixture waspartioned between ethyl acetate and water. The organic layer wasseparated, washed with brine, dried over magnesium sulfate, andevaporated. The residue was chromatographed on silica gel eluting with amixture of ethyl acetate and hexane (1:4) to give ethyl2-benzyl-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (828mg) as an oil.

Ethyl 2-benzyl-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (CDCl₃, δ): 0.70 (3H, t, J=7 Hz), 3.71 (2H, q, J=7 Hz), 4.29 (2H,s), 6.37 (1H, dd, J=1, 4 Hz), 6.85 (1H, dd, J=2, 4 Hz), 7.10-7.30 (7H,m), 7.38-7.46 (2H, m), 7.83 (1H, dd, 1, 2 Hz)

EXAMPLE 188

To a solution of ethyl2-benzyl-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate (730mg) in tetrahydrofuran (10 ml) was added N-chlorosuccinimide (260 mg)and the mixture was stirred at 20° C. for 2 hours. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with aqueous sodium thiosulfate, water and brine,dried over magnesium sulfate, and evaporated. The residue was purifiedby silica gel column chromatograpy eluting with a mixture of toluene andethyl acetate (10:1) to give ethyl2-benzyl-7-chloro-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate(285 mg) as an yellow oil.

Ethyl2-benzyl-7-chloro-4-(4-fluorophenyl)pyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (CDCl₃, δ): 0.69 (3H, t, J=7 Hz), 3.70 (2H, q, J=7 Hz), 4.37 (2H,s), 6.39 (1H, d, J=4 Hz), 6.82 (1H, d, J=4 Hz), 7.10-7.30 (7H, m),7.35-7.45 (2H, m)

EXAMPLE 189

A mixture of ethyl 3-(4-fluorobenzoyl)-4-oxopentanoate (800 mg),1H-pyrrol-1-amine (265 mg), and p-toluenesulfonic acid monohydrate (31mg) in ethanol (5 ml) was refluxed for 5 hours. The mixture waspartioned between ethyl acetate and water. The organic layer wasseparated, washed with brine, dried over magnesium sulfate, andevaporated. The residue was chromatographed on silica gel eluting with amixture of ethyl acetate and hexane (1:4) to giveethyl[4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate(1.09 g) as an oil.

Ethyl [4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 2.45 (3H, s), 3.45 (2H, s), 4.16(2H, q, J=7 Hz), 6.03 (1H, dd, J=1, 4 Hz), 6.72 (1H, dd, J=2, 4 Hz),7.17 (2H, dt, J=2, 7 Hz), 7.40 (2H, ddd, J=2, 5, 7 Hz), 7.68 (1H, dd,J=1, 2 Hz)

EXAMPLE 190

To a solution ofethyl[4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate(100 mg) in tetrahydrofuran (2 ml) was added N-chlorosuccinimide (43 mg)and the mixture was stirred at 20° C. for 2 hours. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with aqueous ethyl acetate, water and brine, driedover magnesium sulfate, and evaporated. The residue was purified bysilica gel column chromatograpy eluting with a mixture of toluene andethyl acetate (10:1) to giveethyl[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate(34 mg) as an yellow oil.

Ethyl[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 2.54 (3H, s), 3.47 (2H, s), 4.16(2H, q, J=7 Hz), 6.05 (1H, d, J=4 Hz), 6.68 (1H, d, J=4 Hz), 7.18 (2H,dt, J=2, 7 Hz), 7.38 (2H, ddd, J=2, 5, 7 Hz)

EXAMPLE 191

To a solution ofethyl[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate(300 mg) in tetrahydrofuran (4 ml) was added 1N sodium hydroxide (1.7ml), followed by methanol (2 ml). After standing at 20° C. overnight,the mixture was partitioned between 1N hydrochloric acid and ethylacetate. The organic layer was separated, washed with water and brine,dried over magnesium sulfate, and evaporated. The residue was trituratedwith ether to give[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]aceticacid (250 mg) as an yellow powder.

[7-Chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]aceticacid

NMR (CDCl₃, δ): 2.57 (3H, s), 3.54 (2H, s), 6.06 (1H, d, J=4 Hz), 6.69(1H, d, J=4 Hz), 7.19 (2H, t, J=7 Hz), 7.38 (2H, dd, J=5, 7 Hz)

EXAMPLE 192

To a solution of[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]aceticacid (220 mg) in tetrahydrofuran (10 ml) was added1,1′-carbonyldiimidazole (18 mg) and the mixture was stirred at 20° C.for 1 hour, then magnesium bis(3-ethoxy-3-oxo-propanoate) (109 mg) wasadded. After the mixture was stirred overnight at 20° C., magnesiumbis(3-ethoxy-3-oxo-propanoate) (109 mg) was added. After stirring for 3hours, the mixture was partitioned between 1N hydrochloric acid andethyl acetate. The organic layer was separated, washed with water andbrine, dried over magnesium sulfate, and evaporated. The residue waschromatographed on silica gel eluting with a mixture of ethyl acetateand hexane (1:5) to give the product (237 mg) as an oil, which wastriturated with ethyl acetate and washed with isopropyl ether to giveethyl4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-oxobutanoate(212 mg) as an yellow powder.

Ethyl4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-oxobutanoate

mp 116-118° C.

NMR (CDCl₃, δ): 1.25 (3H, t, J=7 Hz), 2.46 (3H, s), 3.40 (2H, s), 3.75(2H, s), 4.16 (2H, q, J=7 Hz), 6.04 (1H, d, J=4 Hz), 6.68 (1H, d, J=4Hz), 7.20 (2H, t, J=7 Hz), 7.28 (2H, dd, J=5, 7 Hz)

EXAMPLE 193

To a solution of ethyl4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-oxo-butanoate(160 mg) in methanol (5 ml) was added sodium borohydride (23.4 mg) at 0°C. and the mixture was stirred at the same temperature for 1 hour. Themixture was partitioned between 1N hydrochloric acid and ethyl acetate.The organic layer was separated, washed with water and brine, dried overmagnesium sulfate, and evaporated. The residue was purified bypreparative thin-layer chromatograpy eluting with a mixture of ethylacetate and hexane (1:3) and triturated with ethyl acetate to give ethyl4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoate(95 mg) as an yellow powder.

Ethyl4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 2.18-2.38 (2H, m), 2.67 (3H, s),2.70-2.85 (2H, m), 4.03 (1H, m), 4.09 (2H, q, J=7 Hz), 5.96 (1H, d, J=4Hz), 6.65 (1H, d, J=4 Hz), 7.19 (2H, t, J=7 Hz), 7.30-7.45 (2H, m)

EXAMPLE 194

To a solution of ethyl4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoate(52 mg) in tetrahydrofuran (1 ml) was added 1N sodium hydroxide (0.27ml), followed by methanol (1 ml). After standing at 20° C. overnight,the mixture was partitioned between 1N hydrochloric acid and ethylacetate. The organic layer was separated, washed with water and brine,dried over magnesium sulfate, and evaporated to give4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoicacid (45 mg) as an yellow oil.

4-[7-Chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoicacid

NMR (CDCl₃, δ): 2.125-2.45 (2H, m), 2.66 (3H, s), 2.70-2.88 (2H, m),4.02 (1H, m), 5.97 (1H, d, J=4 Hz), 6.65 (1H, d, J=4 Hz), 7.20 (2H, t,J=7 Hz), 7.30-7.45 (2H, m)

EXAMPLE 195

A mixture of ethyl 7-(4-fluorobenzoyl)-8-oxononanoate (300 mg),(1-amino-5-ethyl-1H-pyrrol-2-yl)(4-fluorophenyl)methanone (216 mg), andp-toluenesulfonic acid monohydrate (35.4 mg) in ethanol (6 ml) wasrefluxed for 5 hours. The mixture was partioned between ethyl acetateand water. The organic layer was separated, washed with brine, driedover magnesium sulfate, and evaporated. The residue was chromatographedon silica gel eluting with a mixture of ethyl acetate and hexane (1:4)to give ethyl6-[7-ethyl-2,4-bis(4-fluorophenyl)pyrrolo[1,2-b]pyridazin-3-yl]hexanoate(83 mg) and ethyl6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate(40 mg) as an oil.

Ethyl6-[7-ethyl-2,4-bis(4-fluorophenyl)pyrrolo[1,2-b]pyridazin-3-yl]hexanoate

NMR (CDCl₃, δ): 0.85-1.00 (2H, m), 1.00-1.10 (2H, m), 1.16-1.30 (2H, m),1.21 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 2.00 (2H, t, J=7 Hz), 2.40(2H, t, J=7 Hz), 3.01 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.97 (1H,d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.12-7.24 (4H, m), 7.38 (2H, dd, J=5,9 Hz), 7.50 (2H, dd, J=5, 9 Hz)

Ethyl6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate

NMR (CDCl₃, δ): 1.15-1.30 (2H, m), 1.23 (3H, t, J=7 Hz), 1.35-1.45 (2H,m), 1.37 (3H, t, J=7 Hz), 1.45-1.55 (2H, m), 2.18 (2H, t, J=7 Hz), 2.40(2H, t, J=7 Hz), 2.54 (3H, s), 3.01 (2H, q, J=7 Hz), 4.10 (2H, q, J=7Hz), 5.85 (1H, d, J=4 Hz), 6.49 (1H, d, J=4 Hz), 7.16 (2H, t, J=9 Hz),7.32 (2H, dd, J=5, 9 Hz)

EXAMPLE 196

A mixture of (1-amino-5-ethyl-1H-pyrrol-2-yl)(4-fluorophenyl)methanone(500 mg), ethyl 8-acetyl-9-oxodecanoate (678 mg), and p-toluenesulfonicacid monohydrate (82 mg) in ethanol (5 ml) was refluxed for 2 hours. Themixture was partioned between ethyl acetate and 1N hydrochloric acid.The organic layer was separated, washed with water and brine, dried overmagnesium sulfate, and evaporated. The residue was chromatographed onsilica gel eluting with toluene to give ethyl6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-eb]pyridazin-3-yl]hexanoate(130 mg) as an oil and[5-ethyl-1-({(1E)-1-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethylidene}amino)-1H-pyrrol-2-yl](4-fluorophenyl)methanone(70 mg) as an yellow crystal.

[5-Ethyl-1-({(1E)-1-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethylidene}amino)-1H-pyrrol-2-yl](4-fluorophenyl)methanone

NMR (CDCl₃, δ): 1.13 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.80-2.00(2H, m), 1.91 (3H, s), 2.86 (3H, s), 3.06 (2H, q, J=7 Hz), 5.97 (1H, d,J=4 Hz), 6.11 (1H, d, J=4 Hz), 6.62 (2H, t, J=4 Hz), 7.11 (4H, t, J=9Hz), 7.48 (2H, dd, J=5, 9 Hz), 7.82 (2H, dd, J=5, 9 Hz)

Ethyl6-[7-ethyl-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate

NMR (CDCl₃, δ): 1.15-1.30 (2H, m), 1.23 (3H, t, J=7 Hz), 1.35-1.45 (2H,m), 1.37 (3H, t, J=7 Hz), 1.45-1.55 (2H, m), 2.18 (2H, t, J=7 Hz), 2.40(2H, t, J=7 Hz), 2.54 (3H, s), 3.01 (2H, q, J=7 Hz), 4.10 (2H, q, J=7Hz), 5.85 (1H, d, J=4 Hz), 6.49 (1H, d, J=4 Hz), 7.16 (2H, t, J=9 Hz),7.32 (2H, dd, J=5, 9 Hz)

EXAMPLE 197

A mixture of ethyl 7-(4-cyanobenzoyl)-8-oxononanoate (2.2 g),2-ethyl-1H-pyrrol-1-amine (809 mg), and p-toluenesulfonic acidmonohydrate (64 mg) in toluene (40 ml) was refluxed for 20 minutes. Themixture was partioned between ethyl acetate and 1N hydrochloric acid.The organic layer was separated, washed with water and brine, dried overmagnesium sulfate, and evaporated. The residue was chromatographed onsilica gel eluting with a mixture of ethyl acetate and hexane (1:5) togive the product, which was triturated with hexane to give ethyl6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo-[1,2-b]pyridazin-3-yl]bexanoate(2.21 g) as an yellow crystals.

Ethyl6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate

NMR (CDCl₃, δ): 1.15-1.25 (2H, m), 1.25 (3H, t, J=7 Hz), 1.30-1.45 (2H,m), 1.38 (3H, t, J=7 Hz), 1.45-1.65 (2H, m), 2.19 (2H, t, J=7 Hz), 2.38(2H, t, J=7 Hz), 2.56 (3H, s), 3.02 (2H, q, J=7 Hz), 4.12 (2H, q, J=7Hz), 5.80 (1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.48 (2H, t, J=9 Hz),7.78 (2H, d, J=9 Hz)

EXAMPLE 198

To a solution of ethyl6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate(15 g) in tetrahydrofuran (15 ml) was added 2N potassium hydroxide (7.4ml), followed by methanol (7.4 ml). After stirring at 50° C. for 2 hoursand 60° C. for 3 hours, the mixture was partitioned between 1Nhydrochloric acid and ethyl acetate. The precipitates were filtered andwashed with ethyl acetate. The organic layer and the washings werecombined, washed with water and brine, dried over magnesium sulfate, andevaporated. The residue was triturated with ethyl acetate and theprecipitates were filtered. The filtrate was purified by silica gelcolumn chromatograpy eluting with a mixture of ethyl acetate and hexane(1:1) and triturated with isopropyl ether to give6-[4-(4-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoicacid (650 mg) as an yellow crystals. The two precipitates were combinedand recrystallized from ethyl acetate to give6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoicacid (550 mg, 37.6%) as an yellow crystals.

6-[4-(4-Cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoicacid

NMR (CDCl₃, δ): 1.15-1.30 (2H, m), 1.35-1.45 (2H, m), 1.38 (3H, t, J=7Hz), 1.45-1.60 (2H, m), 2.26 (2H, t, J=7 Hz), 2.38 (2H, t, J=7 Hz), 2.56(3H, s), 3.02 (2H, q, J=7 Hz), 5.80 (1H, d, J=4 Hz), 6.51 (1H, d, J=4Hz), 7.48 (2H, t, J=9 Hz), 7.79 (2H, d, J=9 Hz)

6-{4-[4-(Aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoicacid

NMR (CDCl₃, δ): 1.1-1.20 (2H, m), 1.29 (3H, t, J=7 Hz), 1.30-1.45 (4H,m), 2.10 (2H, t, J=7 Hz), 2.37 (2H, t, J=7 Hz), 2.51 (3H, s), 2.92 (2H,q, J=7 Hz), 5.73 (1H, d, J=4 Hz), 6.51 (1H, d, J=4 Hz), 7.45 (2H, t, J=9Hz), 7.47 (1H, s), 7.80 (2H, d, J=9 Hz), 8.09 (1H, s)

EXAMPLE 199

To a solution of3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (200 mg) intoluene (6 mL) was added 2,4-pentanedione (837 mg) and p-toluenesulfonicacid monohydrate (32 mg) at ambient temperature. The reaction mixturewas refluxed for 1 hour. The residue was purified by flash silica gelchromatography (silica gel, 80 mL) eluted with hexane-ethyl acetate=10-1to give3-(3-acetyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile(63 mg, 24.8%) as an yellow solid.

3-(3-Acetyl-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl)benzonitrile

NMR (CDCl₃, δ): 1.39 (3H, t, J=8 Hz), 1.95 (3H, s), 2.50 (3H, s), 3.04(2H, q, J=8 Hz), 6.27 (1H, d, J=5 Hz), 6.69 (1H, d, J=5 Hz), 7.59-7.72(2H, m), 7.76-7.84 (2H, m)

MS (ESI⁺): m/z 304 (M+H)

EXAMPLE 200

To a solution of ethyl(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenoate(50 mg) in toluene was added dropwise 1.5 M diisobutylalminum hydride(0.277 mL) in toluene (24 mL) in a dryice-acetone bath. After addition,the mixture was stirred for 2 hours (−10° C.). The reaction mixture wasquenched with sodium, potassium-tartarate and was filtered throughCelite. The organic layer was separated, dried over magnesium sulfate,and evaporated in vacuo. The residue was purified by flash silica gelchromatography (silica gel, 40 mL) eluted with hexane-ethylacetate=10-1, 5-1, and 3-1 to give(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propen-1-olas an yellow solid (30 mg).

(2E)-3-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propen-1-ol

NMR (CDCl₃, δ): 1.38 (6H, d, J=7 Hz), 3.31 (1H, m), 4.05-4.11 (2H, m),5.48 (1H, dt, J=15, 6 Hz), 6.11 (1H, d, J=5 Hz), 6.45 (1H, d, J=15 Hz),6.68 (1H, d, J=5 Hz), 7.08-7.18 (2H, m), 7.29-7.40 (2H, m)

MS (ESI⁻): m/z 345 (M+H)

The following compounds were obtained in substantially the same manneras that of Example 200.

EXAMPLE 201[4-(4-Fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methanol

NMR (CDCl₃, δ): 1.45 (1H, t, J=5 Hz), 2.65 (3H, s), 4.47 (2H, d, J=5Hz), 6.13 (1H, m), 6.73 (1H, m), 7.14-7.28 (2H, m), 7.43-7.51 (2H, m),7.70 (1H, m)

MS (ESI⁺): m/z 257 (M+H)

EXAMPLE 202[7-Ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methanol

NMR (CDCl₃, δ): 1.31-1.46 (10H, m), 3.04 (2H, q, J=8 Hz), 3.46 (1H, m),4.49 (2H, d, J=5 Hz), 6.05 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz),7.12-7.22 (2H, m), 7.41-7.50 (2H, m)

MS (ESI⁺): m/z 313 (M+H)

EXAMPLE 2032-{[7-Ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methoxy}ethanol

NMR (CDCl₃, δ): 1.30-1.45 (9H, m), 3.04 (2H, q, J=8 Hz), 3.35 (1H, m),3.46 (2H, t, J=6 Hz), 3.69 (2H, br t, J=8 Hz), 4.30 (2H, s), 6.07 (1H,d, J=5 Hz), 6.55 (1H, d, J=5 Hz), 7.11-7.22 (2H, m), 7.41-7.51 (2H, m)

MS (ESI⁺): m/z 357 (M+H)

EXAMPLE 204

To a solution of(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propen-1-ol(30 mg) in N,N-dimethylformamide (1 mL) was added 60% sodium hydride inoil (3.8 mg) in an ice-water bath under nitrogen atmosphere. After 20minutes, to the mixture was added methyl iodide (185 mg) at thetemperature. After 15 minutes, the reaction mixture was stirred atambient temperature for 5 hours. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with waterthree times and brine, dried over magnesium sulfate, and evaporated invacuo. The residue was purified by p-TLC (hexane-ethyl acetate=10-1) togive7-chloro-4-(4-fluorophenyl)-2-isopropyl-3-[(1E)-3-methoxy-1-propenyl]pyrrolo[1,2-b]pyridazineas a brown oil (35 mg, 10.2%).

7-Chloro-4-(4-fluorophenyl)-2-isopropyl-3-[(1E)-3-methoxy-1-propenyl]pyrrolo[1,2-b]pyridazine

NMR (CDCl₃, δ): 1.38 (3H, t, J=7 Hz), 3.31 (1H, m), 4.05-4.11 (2H, m),5.48 (1H, dt, J=15, 6 Hz), 6.11 (1H, d, J=5 Hz), 6.45 (1H, d, J=15 Hz),6.68 (1H, d, J=5 Hz), 7.08-7.18 (2H, m), 7.29-7.40 (2H, m)

MS (ESI⁻): m/z 345 (M+H)

EXAMPLE 205

To dimethylsulfoxide (0.5 mL) was added 60% sodium hydride in oil (27mg) and was heated at 60° C. for 40 minutes. To this mixture was added(3-carboxypropyl)(triphenyl)phosphonium bromide (124 mg) at ambienttemperature and was stirred for 40 minutes.7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde(40 mg) was added therein at ambient temperature. After 4 hours, thereaction mixture was acidified with 1N hydrogen chloride and waspartitioned between ethyl acetate and water. The organic layer waswashed with water three times and brine, dried over magnesium sulfate,and evaporated in vacuo. The residue was purified by p-TLC (hexane-ethylacetate=1-1) to give(4E)-5-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-4-pentenoicacid as an yellow oil (21 mg, E:Z=16:1, 56.3%).

(4E)-5-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-4-pentenoicacid

NMR (CDCl₃, δ): 1.40 (6H, d, J=7 Hz), 2.20-2.37 (4H, m), 3.25 (1H, m),5.30 (0.94H, dt, J=15, 7 Hz), 5.01 (0.06H, m), 6.09 (1H, d, J=5 Hz),6.24 (0.94H, d, J=15 Hz), 6.84 (0.06H, d, J=10 Hz), 6.67 (0.94H, d, J=5Hz), 6.70 (0.06H, d, J=5 Hz), 7.07-7.17 (2H, m), 7.26-7.35 (2H, m).

MS (ESI⁻): m/z 385 (M−H)

EXAMPLE 206

To a solution of7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde(40 mg) was added 1N sodium hydroxide (19.3 mg) and acetone (0.425 mL)at ambient temperature. After 8 hours, the reaction mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with water and brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by p-TLC (hexane-ethylacetate=5-1) to give(3E)-4-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-3-buten-2-oneas an yellow solid (33 mg).

(3E)-4-[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-3-buten-2-one

NMR (CDCl₃, δ): 1.40 (6H, d, J=7 Hz), 2.13 (3H, s), 3.38 (1H, m),5.89(1H, d, J=15 Hz), 6.23 (1H, d, J=5 Hz), 6.75 (1H, d, J=5 Hz),7.13-7.23 (2H, m), 7.30-7.39 (2H, m), 7.49 (1H, d, J=15 Hz)

EXAMPLE 207

A solution of ethyl4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate(100 mg) in tetrahydrofuran (1 mL) was purged with nitrogen gas under adryice-acetone bath. To the mixture was added2,2′-azobisisobutyronitrile (0.5 mg) was added to the mixture. After 5minutes, was added 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (43.8mg). The resulting mixture was stirred for 3 hours (−78 to −30° C.).Water (5 mL) was added, and the mixture was extracted with ethylacetate. The organic extract was washed with brine, dried over anhydrousmagnesium sulfate, and evaporated to give an yellow gum. Flash silicagel column chromatography eluting with toluene-hexane=1-5 to 2-3afforded ethyl7-bromo-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylateproduct as an yellow gum (90.0 mg, 72.5%).

Ethyl7-bromo-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (CDCl₃, δ): 0.98 (3H, t, J=7 Hz), 1.40 (6H, d, J=7 Hz), 3.31 (1H,septet, J=7 Hz), 4.05 (2H, q, J=7 Hz), 6.39 (1H, d, J=5 Hz), 6.87 (1H,d, J=5 Hz), 7.16 (2H, t, J=9 Hz), 7.45 (2H, dd, J=4 and 9 Hz)

MS (ESI⁺): m/z 405 (M+H)

EXAMPLE 208

A suspension of sodium hydride (74.4 mg) in dimethylsulfoxide (1.4 mL)was stirred for 1 hour at 60° C. The mixture was added to a solution ofmethyl triphenylphosphonium bromide (1.11 g) in dimethylsulfoxide (1.0mL) at room temperature. After stirring for 0.5 hour, the mixture wasadded ethyl4-(4-fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate(500 mg). After stirring for 15 hours, the mixture was partitionedbetween ethyl acetate (20 mL) and water (5 mL). The organic layer waswashed with water and brine, dried over anhydrous magnesium sulfate, andevaporated to give an orange gum. Flash silica gel column chromatographyeluting with ethyl acetate-hexane=1-7 to 3-1 afforded ethyl4-(4-fluorophenyl)-2-isopropyl-7-vinylpyrrolo[1,2-b]pyridazine-3-carboxylatean yellow gum, which was solidified upon standing (361 mg, 72.6%).

Ethyl4-(4-fluorophenyl)-2-isopropyl-7-vinylpyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (CDCl₃, δ): 0.97 (3H, t, J=7 Hz), 1.38 (6H, d, J=7 Hz), 3.32 (1H,septet, J=7 Hz), 4.03 (2H, q, J=7 Hz), 5.35 (1H, dd, J=2 and 12 Hz),6.11 (1H, dd, J=2 and 18 Hz), 6.34 (1H, d, J=5 Hz), 6.99 (1H, d, J=5Hz), 7.16 (1H, t, J=9 Hz), 7.25 (1H, dd, J=12 and 18 Hz), 7.45 (2H, d,J=4 and 9 Hz)

EXAMPLE 209

To a solution of ethyl7-{4-[4-({[(benzyloxy)carbonyl]-amino}sulfonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoate(169 mg) in ethanol (2 mL) was added 10% palladium on activated carbon(1.6 mg), and the mixture was stirred under hydrogen pressure (3 kg/cm2)for 2 hours. The resulting mixture was filtered through celite, and thefiltrate was concentrated to give an yellow gum. Preparative silica gelthin layer chromatography eluting with ethyl acetate-hexane=1-1 affordedethyl7-{4-[4-(aminosulfonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoateas an yellow gum (76.8 mg, 58.4%).

Ethyl7-{4-[4-(aminosulfonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}heptanoate

NMR (CDCl₃, δ): 1.07-1.25 (7H, m), 1.30-1.46 (7H, m), 2.18 (2H, t, J=7Hz), 2.36 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=7 Hz), 4.12 (2H, q, J=7Hz), 5.21 (2H, s), 5.82 (1H, d, J=5 Hz), 6.50 (1H, d, J=5 Hz), 7.52 (2H,d, J=9 Hz), 8.05 (2H, d, J=9 Hz)

MS (ESI⁺): m/z 472 (M+H)

EXAMPLE 210

To a solution of ethyl4-(4-cyanophenyl)-2-(2-ethoxy-2-oxoethyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate(77.9 mg) in ethanol (0.5 mL)-tetrahydrofuran (0.5 mL) was added 1Npotassium hydroxide. The resulting solution was stirred for 2.5 hours atroom temperature. The mixture was stirred for futher 1 hour after adding1N potassium hydroxide (0.04 mL). The reaction was quenched by adding 1Nhydrochloric acid (0.23 mL). The volatile was evaporated off, and theresulting residue was partitioned between ethyl acetate (10 mL) and 1Nhydrochloric acid (6 mL). The organic layer was washed with brine,dried, and evaporated to give[4-(4-cyanophenyl)-3-(ethoxycarbonyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]aceticacid as an yellow solid (67.7 mg, 93.4%).

[4-(4-Cyanophenyl)-3-(ethoxycarbonyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]aceticacid

NMR (CDCl₃, δ): 0.84 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 3.05 (2H, q,J=7 Hz), 3.93 (2H, q, J=7 Hz), 4.18 (3H, s), 6.27 (1H, d, J=5 Hz), 6.74(1H, d, J=5 Hz), 7.52 (2H, d, J=9 Hz), 7.76 (2H, d, J=9 Hz)

MS (ESI⁺): m/z 378 (M+H)

EXAMPLE 211

To a solution of ethyl2-(2-amino-2-oxoethyl)-4-(4-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate(35.0 mg) in tetrahydrofuran (1 mL) was added 60% sodium hydride (4.50mg) under an ice-bath. The resulting mixture was stirred for 1 hour. Thereaction was quenched by adding 1N HCl (4 mL). The mixture was extractedwith ethyl acetate (10 mL), and the organic layer was washed with waterand brine, dried over magnesium sulfate, and evaporated. Preparativesilica gel thin layer chromatography eluting with ethylchloroform-methanol=10-1 afforded4-(7-ethyl-1,3-dioxo-1,2,3,4-tetrahydropyrido[3,4-e]pyrrolo[1,2-b]-pyridazin-10-yl)benzonitrileas an yellow solid (3.86 mg, 12.6%).

4-(7-Ethyl-1,3-dioxo-1,2,3,4-tetrahydropyrido[3,4-e]pyrrolo[1,2-b]pyridazin-10-yl)benzonitrile

NMR (CDCl₃, δ): 1.40 (3H, t, J=7 Hz), 3.08 (2H, q, J=7 Hz), 4.16 (3H,s), 6.38 (1H, d, J=5 Hz), 6.85 (1H, d, J=5 Hz), 7.46 (2H, d, J=9 Hz),7.78 (2H, d, J=9 Hz), 7.92 (1H, s, br)

EXAMPLE 212

To methanol (1 mL) was added 60% sodium hydride (651 mg) at roomtemperature. Then,4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yltrifluoromethanesulfonate (70.0 mg) was added to the mixture. Theresulting mixture was stirred for 2 hours at room temperature and 1 hourat 50° C. The mixture was partitioned between ethyl acetate and water.The organic layer was washed with brine, dried over magnesium sulfate,and evaporated. Preparative silica gel thin layer chromatography elutingwith ethyl acetate-hexane=1-1 afforded3-[7-ethyl-2-methoxy-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrileas an yellow solid (1.92 mg, 3.7%).

3-[7-Ethyl-2-methoxy-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.38 (3H, t, J=7 Hz), 3.01 (2H, q, J=7 Hz), 3.24 (3H,s), 4.18 (3H, s), 6.12 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.53-7.64(3H, m), 7.76 (1H, m)

EXAMPLE 213

To a solution of ethyl4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylate(92.6 mg) in tetrahydrofuran (1 mL) and ethanol (0.5 mL) was added 1Nsodium hydroxide (0.349 mL). The resulting mixture was stirred for 3hours at room temperature. The resulting mixture was stirred further for40 minutes after adding 1N sodium hydroxide (0.1 mL). The mixture wasstirred further for 1.5 hours after adding 1N sodium hydroxide (0.1 mL).The reaction was quenched by adiding 1N hydrochloric acid (1 mL), andthe mixture was partitioned between ethyl acetate (20 mL) and water (10mL). The organic layer was washed with brine, dried over magnesiumsulfate, and evaporated to give a red oil. Flash silica gel columnchromatography eluting with ethyl acetate-hexane=1-1 afforded3-(6-ethyl-1,1-dioxido-3-oxo-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrileas a red foam (52.4 mg, 64.0%).

3-(6-Ethyl-1,1-dioxido-3-oxo-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile

NMR (CDCl₃, δ): 1.45 (3H, t, J=7 Hz), 3.21, (3H, s), 4.28 (2H, s), 6.91(1H, d, J=5 Hz), 7.26 (1H, d, J=5 Hz), 7.75 (1H, t, J=9 Hz), 7.91 (1H,d, J=9 Hz), 8.08-8.16 (2H, m)

MS (ESI⁺): m/z 352 (M+H)

EXAMPLE 214

To a solution of3-(6-ethyl-1,1-dioxido-3-oxo-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile(60.0 mg) in tetrahydrofuran (0.2 mL) was added 1 M solution ofborane-tetrahydrofuran complex in tetrahydrofuran (0.487 mL) under anice-bath. After stirring for 1 hour, the reaction was quenched by adding1N hydrochloric acid (1 mL). The mixture was partitioned between ethylacetate (20 mL) and water (10 mL), and the organic layer was washed withbrine, dried, and evaporated to give3-(6-ethyl-3-hydroxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)-benzonitrileas an yellow foam (576 mg, 99.8%).

3-(6-Ethyl-3-hydroxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile

NMR (CDCl₃, δ): 1.45 (3H, t, J=7 Hz), 3.21, (3H, s), 4.28 (2H, s), 6.91(1H, d, J=5 Hz), 7.26 (1H, d, J=5 Hz), 7.75 (1H, t, J=9 Hz), 7.91 (1H,d, J=9 Hz), 8.08-8.16 (2H, m)

EXAMPLE 215

To a solution of3-(6-ethyl-3-hydroxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile(54.0 mg) in tetrahydrofuran (1 mL) was added 60% sodium hydride (6.69mg) under an ice-bath. After stirring for 0.5 hour, methyl iodide (25.9mg) was added, and the mixture was stirred for 3 hours 20 minutes atroom temperature. The mixture was stirred for another 6 hours afteradding mehtyl iodide (25.9 mg). The mixture was further stirred for 1hour after adding 60% sodium hydride (3.0 mg) and methyl iodide (25.9mg). The mixture was partitioned between ethyl acetate and 1Nhydrochloric acid, and the organic layer was washed with brine, driedover magnesium sulfate, and evaporated to give an yellow oil.Preparative silica gel thin layer chromatography eluting with ethylacetate-hexane=1-2 afforded3-(6-ethyl-1,1-dioxidopyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile(5.9 mg, 10.5%, an yellow solid) and3-(6-ethyl-3-methoxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile(16.8 mg, 30.0%, an orange gum).

3-(6-Ethyl-1,1-dioxidopyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile

NMR (CDCl₃, δ): 1.40 (3H, t, J=7 Hz), 3.07 (2H, q, J=7 Hz), 6.68 (1H, d,J=5 Hz), 6.82 (1H, d, J=5 Hz), 7.02 (1H, d, J=7 Hz), 7.37 (1H, d, J=7Hz), 7.72 (1H, t, J=9 Hz), 7.87 (1H, d, J=9 Hz), 8.11-8.16 (2H, m)

3-(6-Ethyl-3-methoxy-1,1-dioxido-2,3-dihydropyrrolo[1,2-b]thieno[2,3-e]pyridazin-9-yl)benzonitrile

NMR (CDCl₃, δ): 1.42 (3H, t, J=7 Hz), 3.12 (2H, q, J=7 Hz), 3.67 (3H,s), 3.73 (2H, m), 5.02 (1H, m), 6.74 (1H, d, J=5 Hz), 6.97 (1H, d, J=5Hz), 7.70 (1H, t, J=9 Hz), 7.85 (1H, d, J=9 Hz), 8.04-8.13 (2H, m)

MS (ESI⁺): m/z 368 (M+H)

EXAMPLE 216

A mixture of 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile(1.00 g), ethyl 3-(methylsulfonyl)-2-oxopropanoate (1.34 g), andp-toluenesulfonic acid monohydrate (795 mg) in toluene (20 mL) wasrefluxed for 1 hour with Dean-Stark condenser. The volatile was removedin vacuo. Flash silica gel column chromatography eluting with ethylacetate-hexane=1-10 to 9-15 afforded the intermediate imine (1.38 g,67.7%) as an orange foam. The foam was dissolved in N-methylmorpholine(10 mL), and the solution was stirred for 1 hour at 130° C. The mixturewas partitioned between ethyl acetate (50 mL) and water (30 mL). Theorganic layer was washed with water (30×2 mL) and brine, dried overmagnesium sulfate, and evaporated to give a dark orange solid. The solidwas triturated in diisopropyl ether (10 mL) to give2-(trimethylsilyl)ethyl4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylateas an yellow powder (1.11 g, 67.7%).

2-(Trimethylsilyl)ethyl4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylate

NMR (CDCl₃, δ): 0.12 (9H, s), 1.22 (2H, m), 1.39 (3H, t, J=7 Hz), 3.09(2H, q, J=7 Hz), 3.23 (3H, s), 4.53 (2H, m), 6.30 (1H, d, J=5 Hz), 6.89(1H, d, J=5 Hz), 7.50-7.67 (3H, m), 7.82 (1H, m)

MS (ESI⁺): m/z 470 (M+H)

The following compound was obtained in substantially the same manner asthat of Example 216.

EXAMPLE 217 Ethyl4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylate

NMR (CDCl₃, δ): 1.39 (3H, t, J=7 Hz), 1.47 (3H, t, J=7 Hz), 3.10 (2H, q,J=7 Hz), 3.21, (3H, s), 4.51 (2H, q, J=7 Hz), 6.30 (1H, d, J=5 Hz), 6.90(1H, d, J=5 Hz), 7.61-7.67 (3H, m), 7.72 (1H, m)

EXAMPLE 218

A solution of 2-(trimethylsilyl)ethyl4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylate(1.09) in trifluoroacetic acid (5 mL) was stirred for 1.5 hours under anice-bath. The reaction was quenched by adding water (20 mL). An yellowcrystal was formed upon the addition, which was collected by filtration.The crystal was washed with water (5 mL) and hexane (3 mL) to give4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylicacid as an yellow crystal (756 mg, 88.2%).

4-(3-Cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylicacid

NMR (CDCl₃, δ): 1.41 (2H, m), 3.10 (2H, q, J=7 Hz), 3.30 (3H, s), 6.36(1H, d, J=5 Hz), 6.94 (1H, d, J=5 Hz), 7.53-7.67 (3H, m), 7.82 (1H, m)

MS (ESI⁺): m/z 370 (M+H)

EXAMPLE 219

A mixture of4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylicacid (40.0 mg), diemthylamine hydrochloride (12.4 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (25.2 mg), and1-hydroxybenzotriazole (21.9 mg) in N,N-dimethylformamide (1 mL) wasstirred for 3 hours at room temperature. The mixture was partitionedbetween ehtyl acetate (20 mL) and 1N hydrochloric acid (10 mL). Theorganic layer was washed with water (10×3 mL), saturated sodiumbicarbonate (10 mL), and brine, dried over magnesium sulfate, andevaporated to give4-(3-cyanophenyl)-7-ethyl-N,N-dimethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxamideas an yellow solid (43.4 mg, 101%).

4-(3-Cyanophenyl)-7-ethyl-N,N-dimethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxamide

NMR (CDCl₃, δ): 1.38 (2H, m), 3.07 (2H, q, J=7 Hz), 3.12 (3H, s), 3.18(3H, s), 3.27 (3H, s), 6.27 (1H, d, J=5 Hz), 6.85 (1H, d, J=5 Hz),7.57-7.67 (3H, m), 7.81 (1H, m)

MS (ESI⁺): m/z 397 (M+H)

EXAMPLE 220

A mixture of ethyl4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carboxylate(450 mg) and 85% potassium hydroxide (3.01 g) in a mixture of ethanol (3mL) and water (2 mL) was refluxed for 25 hours. The reaction mixture wascooled under an ice-bath, and quenched by adding concentratedhydrochloric (5 mL). The mixture was partitioned between ethyl acetate(20 mL) and water (10 mL), and the organic layer was washed with brine,dried over magnesium sulfate, and evaporated to give an yellow solid(388 mg). The solid was triturated in hexane to give4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carboxylicacid as an yellow powder (361 mg, 86.4%).

4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carboxylicacid

NMR (CDCl₃, δ): 1.41 (3H, t, J=7 Hz), 3.08 (2H, q, J=7 Hz), 6.37 (1H, d,J=5 Hz), 6.55 (1H, m), 6.76 (1H, d, J=5 Hz), 7.02 (1H, d, J=3 Hz),7.40-7.55 (5H, m)

MS (ESI⁺): m/z 367 (M+H)

EXAMPLE 221

To a solution of4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carboxylicacid (358 mg) and N,N-dimethylformamide (1.39 mg) in dichloromethane (3mL) was added oxalyl chloride (157 mg) at room temperature. Afterstirring for 30 minutes, the volatile was removed in vacuo, and theresidue was azeotroped with toluene three times to afford4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carbonylchloride as an yellow gum (396 mg, 106%).

4-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carbonylchloride

NMR (CDCl₃, δ): 1.42 (3H, t, J=7 Hz), 3.10 (2H, q, J=7 Hz), 6.45 (1H, d,J=5 Hz), 6.59 (1H, m), 6.82 (1H, d, J=5 Hz), 7.06 (1H, d, J=7 Hz),7.38-7.55 (4H, m), 7.63 (1H, m)

EXAMPLE 222

To a solution of methyl aminoacetate hydrochloride (26.1 mg) andtriethylamine (42.0 mg) in dichloromethane (0.5 mL) was added a solutionof4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carbonylchloride (40.0 mg) in dichloromethane (0.5 mL) under an ice-bath. Themixture was partitioned between ethyl acetate (20 mL) and 1Nhydrochloric acid (10 mL), and the organic layer was washed with brine(10 mL), dried over magnesium sulfate, and evaporated to give methyl({[4-(3-chlorophenyl)-7-ethyl-2-(3-furyl)pyrrolo[1,2-b]pyridazin-3-yl]carbonyl}amino)acetateas an yellow gum (50.6 mg, 111%).

Methyl({[4-(3-chlorophenyl)-7-ethyl-2-(3-furyl)pyrrolo[1,2-b]pyridazin-3-yl]carbonyl}amino)acetate

NMR (CDCl₃, δ): 1.41 (3H, t, J=7 Hz), 3.10 (2H, q, J=7 Hz), 3.69 (3H,s), 3.95 (2H, d, J=5 Hz), 6.01 (1H, t, br, 5 Hz), 6.35 (1H, d, J=5 Hz),6.51 (1H, m), 6.75 (1H, d, J=5 Hz), 7.01 (1H, d, J=7 Hz), 7.37-7.48 (3H,m), 7.53 (1H, m), 7.58 (1H, m)

MS (ESI⁺): m/z 438 (M+H)

The following compound was obtained in substantially the same manner asthat of Example 222.

EXAMPLE 2234-(3-Chlorophenyl)-7-ethyl-2-(2-furyl)-N,N-bis(2-hydroxyethyl)pyrrolo[1,2-b]pyridazine-3-carboxamide

NMR (CDCl₃, δ): 1.42 (3H, t, J=7 Hz), 2.35-2.72 (4H, m), 3.08 (2H, d,J=5 Hz), 3.20-3.63 (4H, m), 3.82 (2H, m), 6.40 (1H, t, br, 5 Hz), 6.54(1H, m), 6.75 (1H, d, J=5 Hz), 7.04 (1H, d, J=3 Hz), 7.40-7.48 (2H, m),7.53-7.60 (2H, m), 7.71 (1H, m)

MS (ESI⁺): m/z 454 (M+H)

EXAMPLE 224

To a solution of3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoicacid (100 mg) in dioxane (0.5 mL) was added triethylamine (25.2 mg)followed by a solution of pivaloyl chloride (30.1 mg) in dioxane (0.5mL). A white precipitate was formed. After stirring for 40 minutes atroom temperature, the precipitate was removed by filtration, and washedwith dioxane (2 mL). To the combined washing was added a solution of2-aminoethanesulfonic acid (38.6 mg) in 1N sodium hydroxide (0.247 mL).The resulting mixture was stirred for 1 hour at room temperature. Themixture was partitioned between ethyl acetate (15 mL) and water (5 mL).The organic layer was washed with brine, dried over magnesium sulfate,and evaporated. Preparative silica gel thin layer chromatography elutingwith chloroform-methanol=5-1 afforded2-({3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo-[1,2-b]pyridazin-3-yl]propanoyl}amino)ethanesulfonicacid as an yellow solid (104 mg, 82.0%).

2-({3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoyl}amino)ethanesulfonicacid

NMR (CDCl₃, δ): 1.27 (5H, m), 2.59 (4H, m), 2.90-3.14 (4H, m), 5.96 (1H,m), 6.06 (1H, m), 7.06-7.40 (9H, m)

EXAMPLE 225

A solution of3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoicacid (100 mg),(2R,3R,4S,5S,6R)-2-amino-3,5-bis[(2,2-dimethylpropanoyl)oxy]-6-{[(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-pyran-4-ylpivalate (255 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.494mmol), and 1-hydroxybenzotriazole (66.7 mg) in N,N-dimethylformamide (1mL) was stirred for 1 hour at room temperature. The mixture waspartitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10mL). The organic layer was washed with water (10×3 mL), saturated sodiumbicarbonate (10 mL), and brine, dried over magnesium sulfate, andevaporated to give an yellow foam (339 mg). Flash silica gel columnchromatography eluting with ethyl acetate-hexane=1-10 to 2-5 afforded(2R,3R,4S,5S,6R)-2-({3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoyl}amino)-3,5-bis[(2,2-dimethylpropanoyl)oxy]-6-{[(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-pyran-4-ylpivalate an yellow foam (240 mg, 108%).

(2R,3R,4S,5S,6R)-2-({3-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoyl}amino)-3,5-bis[(2,2-dimethylpropanoyl)oxy]-6-{[(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-pyran-4-ylpivalate

NMR (CDCl₃, δ): 0.97-1.26 (3H, m), 1.35 (3H, t, J=7 Hz), 1.83 (2H, m),2.81 (2H, m), 3.01 (2H, q, J=7 Hz), 3.87-4.16 (3H, m), 4.90-5.27 (3H,m), 5.36-5.51 (2H, m), 6.01 (1H, d, J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.29(1H, m), 7.40-7.59 (8H, m)

EXAMPLE 226

To a solution ofethyl[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]acetate(114 mg) in tetrahydrofuran (2 mL) was added 1 M diisobutylaluminumhydride in toluene (0.816 mL) under an ice-bath. After stirring for 1hour at room temperature, additional 1 M diisobutylaluminum hydride(0.41 mL) was added. The reaction was quenched by adding 1N hydrochloricacid (1 mL) after 1 hour. The mixture was partitioned between ethylacetate (20 mL) and 1N hydrochloric acid (10 mL), and filtered throughcelite. The organic layer was washed with water (10 mL) and brine, driedover magnesium sulfate, and evaporated to give an yellow gum. Flashsilica gel column chromatography eluting with ethyl acetate-hexane=1-20to 2-50 afforded2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethanolas an yellow oil, which was crystalyzed upon standing (107 mg, 104%).

2-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethanol

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 2.77 (2H, t, J=7 Hz), 3.01 (2H, q,J=7 Hz), 3.26 (2H, m), 3.26 (2H, m), 6.00 (1H, d, J=5 Hz), 6.63 (1H, d,J=5 Hz), 7.34 (1H, m), 7.41-7.55 (8H, m)

EXAMPLE 227

To a mixture of2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethanol(105 mg), 2,3,4,6-tetra-O-acetyl-beta-D-galactosyl bromide (299 mg),silver carbonate (154 mg) in toluene (2 mL) was added silver triflate(3.58 mg) under an ice bath. After 40 minutes,2,3,4,6-tetra-O-acetyl-beta-D-galactosyl bromide (114 mg), silvercarbonate (229 mg) was added, and the mixture was stirred for 50minutes. The mixtrure was further stirred for 50 minutes after adding2,3,4,6-tetra-O-acetyl-beta-D-galactosyl bromide (114 mg), silvercarbonate (154 mg). The mixture was filtered through celite, and thefiltrate was paritiotned between ethyl acetate and water. The organiclayer was washed with brine, dried over magnesium sulfate, andevaporated to give an yellow gum. Flash silica gel column chromatographyeluting with ethyl acetate-hexane=1-10 to 7/10 afforded(2R,3R,4S,5S,6R)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}tetrahydro-2H-pyran-3-ylacetate as an yellow gum (115 mg, 58.4%).

(2R,3R,4S,5S,6R)-4,5-bis(Acetyloxy)-6-[(acetyloxy)methyl]-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}tetrahydro-2H-pyran-3-ylacetate

NMR (CDCl₃, δ): 1.35 (3H, t, J=7 Hz), 1.70 (3H, m), 1.94 (3H, s), 2.04(3H, s), 2.11 (3H, s), 2.78 (2H, m), 3.01 (2H, q, J=7 Hz), 3.10 (1H, m),3.46 (1H, m), 3.62 (1H, t, J=6 Hz), 3.79 (1H, d, J=8 Hz), 3.98 (2H, m),4.83 (1H, dd, J=3 and 10 Hz), 4.97 (1H, dd, J=8 and 10 Hz), 5.28 (1H, d,J=3 Hz), 6.02 (1H, d, J=5 Hz), 6.64 (1H, d, J=5 Hz), 7.31 (1H, m),7.41-7.56 (8H, m)

EXAMPLE 228

To a solution of(2R,3R,4S,5S,6R)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}tetrahydro-2H-pyran-3-ylacetate (113 mg) in methanol (2 mL) was added sodium methoxide (0.86 mg)at room temperature. After stirring for 2 hours, the solvent wasevaporated off, and the mixture was partitioned between ethyl acetate(20 mL) and water (10 mL). The organic layer was washed with brine,dried over magnesium sulfate, and evaporated to give an yellow foam(77.3 mg). The foam was triturated in hexane to give(2R,3R,4S,5R,6R)-2-{2-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolas an yellow powder (48.3 mg, 89.7%).

(2R,3R,4S,5R,6R)-2-{2-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

NMR (CDCl₃, δ): 1.36 (3H, t, J=7 Hz), 1.92 (1H, m), 2.06 (1H, m), 2.56(1H, s, br), 2.76-2.92 (3H, m), 3.02 (2H, q, J=7 Hz), 3.24 (2H, m),3.38-3.50 (3H, m), 3.63-3.84 (3H, m), 2.41 (1H, s, br), 6.01 (1H, d, J=5Hz), 6.63 (1H, d, J=5 Hz), 7.32 (1H, m), 7.41-7.57 (8H, m)

The following compounds were obtained in substantially the same manneras that of Example 228.

EXAMPLE 2293-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]propanamide

NMR (CDCl₃, δ): 1.38 (3H, t, J=7 Hz), 1.97 (2H, m), 2.83 (2H, m), 3.01(2H, q, J=7 Hz), 3.31-3.52 (3H, m), 3.61-3.76 (2H, m), 3.88 (1H, m),4.63 (1H, d, J=9 Hz), 6.01 (1H, d, J=5 Hz), 6.64 (1H, d, J=5 Hz), 7.34(1H, m), 7.42-7.59 (8H, m)

EXAMPLE 230 Ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoatefrom ethyl5-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.34-1.50 (5H, m), 154 (2H, m),2.19 (2H, t, J=7 Hz), 2.37 (2H, m), 3.02 (2H, q, J=7 Hz), 3.71 (1H, t,J=5 Hz), 4.10 (2H, q, J=7 Hz), 4.86 (2H, d, J=5 Hz), 5.97 (1H, d, J=5Hz), 6.60 (1H, d, J=5 Hz), 7.88 (1H, m), 8.55 (1H, m), 8.79 (1H, m)

EXAMPLE 231

To a solution of5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid (50 mg) in N,N-dimethylformamide (1 mL) was added1,1′-carbonyldiimidazole (33.6 mg) at ambient temperature. After 1 hourstirring, to the mixture was added methanesulfonamide (19.7 mg) and1,8-diazabicyclo[5.4.0]undec-7-ene (31.6 mg). The mixture was heated at50° C. for 2 hours. The reaction mixture was partitioned between ethylacetate and water. The aqueous layer was acidified with 1N hydrogenchloride and was extracted with ethyl acetate. The organic layer waswashed with water 3 times and brine, dried over magnesium sulfate, andevaporated in vacuo to give an yellow solid. The residue wascrystallized from IPE to give yellow solid (45 mg). The solid wasrecrystallized from ethanol to giveN-{5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide(25 mg) as an yellow solid.

N-{5-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide

NMR (CDCl₃, δ): 1.33-1.61 (7H, m), 2.21 (2H, t, J=8 Hz), 2.40 (2H, t,J=8 Hz), 2.55 (3H, s), 3.00 (2H, q, J=8 Hz), 3.29 (3H, s), 5.80 (1H, d,J=5 Hz), 6.52 (1H, d, J=5 Hz), 7.58-7.67 (3H, m), 7.76 (1H, m), 7.86(1H, br s)

MS (ESI⁺): m/z 439 (M+H)

EXAMPLE 232

To a solution of ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate(45 mg) in tetrahydrofuran (1 mL) was added lithium borohydride (5 mg)in an ice-water bath. Then the reaction mixture was stirred at ambienttemperature. After 2 hours, another lithium borohydride (5 mg) was addedtherein and was stirred overnight. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried over magnesium sulfate, and was evaporated in vacuo. Theresidue was purified by p-TLC (hexane-ethyl acetate=1-1) to give3-[7-ethyl-3-(6-hydroxyhexyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile(26 mg, 64.5%) as an yellow oil and6-{4-[3-(aminomethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}-1-hexanol(13 mg, 31.9%) as a yello solid.

3-[7-Ethyl-3-(6-hydroxyhexyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.15-1.53 (11H, m), 2.32-2.41 (2H, m), 2.56 (3H, s),3.01 (2H, q, J=8 Hz), 3.58 (2H, br t, J=8 Hz), 5.58 (1H, br t, J=8 Hz),5.79 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.57-7.63 (2H, m), 7.65 (1H,br s), 7.75 (1H, m)

MS (ESI⁺): m/z 362 (M+H)6-{4-[3-(Aminomethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}-1-hexanol

NMR (CDCl₃, δ): 1.03-1.43 (11H, m), 2.41 (2H, t, J=8 Hz), 2.55 (3H, s),3.01 (2H, q, J=8 Hz), 3.39-3.61 (2H, m), 3.88-4.04 (2H, m), 4.25 (2H, brs), 5.31 (1H, d, J=5 Hz), 6.49 (1H, d, J=5 Hz), 7.28-7.40 (3H, m), 7.51(1H, t, J=8 Hz)

MS (ESI⁺): m/z 366 (M+H)

EXAMPLE 233

To a suspension of6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoicacid (590 mg) in water (3 mL) was added 1N sodium hydroxide (15 mL) atambient temperature. After 5 hours, the mixure became clear solution.The solution was filtered through membrane filter, washed with water(0.4 mL×3), and was freeze dried for 15 hours to give6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoicacid sodium salt (612 mg, 98.2%) as a pale yellow powder.

6-{4-[4-(Aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoicacid sodium salt

NMR (DMSO-d₆, δ): 1.10-1.15 (2H, m), 1.20-1.40 (7H, m), 1.74 (2H, t, J=8Hz), 2.25-2.38 (2H, m), 2.50 (3H, s), 2.91 (2H, q, J=8 Hz), 5.72 (1H, d,J=5 Hz), 6.50 (1H, d, J=5 Hz), 7.39-7.46 (3H, m), 7.97 (2H, d, J=8 Hz),8.26 (1H, br s)

EXAMPLE 234

A solution of5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid (100 mg), triethylamime (29.4 mg), and diphenylphosphoryl azide(79.9 mg) in tert-butanol (2 mL) was heated at 80° C. for 8 hours. Thecooled reaction mixture was partitioned between ethyl acetate and water.The aqueous layer was extracted with ethyl acetate. The combined organiclayer was washed with brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by p-TLC (hexane-ethylacetate=3-1) to give tert-butyl4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butylcarbamate(28 mg, 23.4%) as an yellow oil.

tert-Butyl4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butylcarbamate

NMR (CDCl₃, δ): 1.27-1.47 (14H, m), 2.34-2.45 (2H, m), 2.55 (3H, s),2.91-3.02 (4H, m), 4.39 (1H, br s), 5.79 (1H, d, J=5 Hz), 6.51 (1H, d,J=5 Hz), 7.56-7.67 (3H, m), 7.75 (1H, m)

MS (ESI⁺): m/z 433 (M+H)

EXAMPLE 235

To tert-butyl4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butylcarbamate(25 mg) was added 4N hydrogen chloride in ethyl acetate (1 mL) atambient temperature. After 1 hour, the mixture was evaporated in vacuo.The residue was triturated with isopropyl ether to give3-[3-(4-aminobutyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrilehydrochloride as dark green amorphous (18 mg).

3-[3-(4-Aminobutyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrilehydrochloride

NMR (CDCl₃, δ): 1.27-1.47 (14H, m), 2.34-2.45 (2H, m), 2.55 (3H, s),2.91-3.02 (4H, m), 4.39 (1H, br s), 5.79 (1H, d, J=5 Hz), 6.51 (1H, d,J=5 Hz), 7.56-7.67 (3H, m), 7.75 (1H, m)

MS (ESI⁺): m/z 333 (M+H)

EXAMPLE 236

To lithium chloride (165 mg) was added a solution of ethyl5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate(65 mg) and tributyl(vinyl)stannane (56.7 mg) in dioxane (1 mL) andtetrakis(triphenylphosphine)palladium(0) (1.9 mg). The mixture wasrefluxed. After 4 hours, tributyl(vinyl)stannane (50 mg) andtetrakis(triphenylphosphine)palladium(0) (1.9 mg) was added. Afterrefluxed over night, the reaction mixture was quenched with potassiumfluoride (1.8 mmol) in H₂O. The mixture was filtered through Celite andwas washed with ethyl acetate. The organic layer was separated, washedwith water and brine, dried over magnesium sulfate, and evaporated invacuo. The residue was purified by flash silica gel chromatography(silica gel, 50 mL) eluted with hexane-ethyl acetate=5-1 and 3-1 to giveethyl5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(18 mg, 28.3%) as an yellow oil.

Ethyl5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.15-1.70 (10H, m), 2.18 (2H, t, J=8 Hz), 2.36-2.46 (2H,m), 2.55 (3H, s), 3.00 (2H, q, J=8 Hz), 4.08 (2H, q, J=8 Hz), 5.54 (1H,d, J=10 Hz), 5.86 (1H, d, J=5 Hz), 6.25 (1H, d, J=16 Hz), 6.51 (1H, d,J=5 Hz), 6.87 (1H, dd, J=16, 10 Hz), 7.16 (1H, dd, J=6, 1 Hz), 7.33 (1H,br s), 8.70 (1H, d, J=6 Hz)

MS (ESI⁺): m/z 392 (M+H)

The following compounds were obtained in substantially the same manneras that of Example 236.

EXAMPLE 237 Ethyl5-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.42 (3H, t,J=7 Hz), 1.40-1.60 (4H, m), 2.20 (2H, t, J=7 Hz), 2.38-2.52 (2H, m),2.56 (3H, s), 3.03 (2H, q, J=7 Hz), 3.96 (2H, q, J=7 Hz), 4.09 (2H, q,J=7 Hz), 4.34 (1H, d, J=2 Hz), 4.76 (1H, d, J=2 Hz), 5.87 (1H, d, J=4Hz), 6.52 (1H, d, J=4 Hz), 7.89 (1H, m), 8.53 (1H, d, J=2 Hz), 8.93 (1H,d, J=2 Hz)

MS: (m/z) 436 (M+H)

EXAMPLE 238 Ethyl5-[7-ethyl-2-methyl-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.65(4H, m), 2.18 (2H, t, J=7 Hz), 2.40-2.53 (2H, m), 2.56 (3H, s), 3.02(2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 5.43 (1H, d, J=11 Hz), 5.88 (1H,d, J=4 Hz), 5.89 (1H, d, J=18 Hz), 6.52 (1H, d, J=4 Hz), 6.71-6.83 (1H,dd, J=11 Hz, 18 Hz), 7.73 (1H, m), 8.47 (1H, d, J=2 Hz), 8.68 (1H, d,J=2 Hz)

EXAMPLE 239 Ethyl5-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.60(4H, m), 2.17 (2H, t, J=7 Hz), 2.52-2.65 (2H, m), 3.04 (2H, q, J=7 Hz),3.46 (3H, s), 4.08 (2H, q, J=7 Hz), 4.63 (2H, s), 5.43 (1H, d, J=11 Hz),5.88 (1H, d, J=18 Hz), 5.91 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz),6.71-6.83 (1H, dd, J=11 Hz, 18 Hz), 7.75 (1H, m), 8.49 (1H, d, J=2 Hz),8.71 (1H, d, J=2 Hz)

EXAMPLE 240 Ethyl5-[4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.42 (3H, t,J=7 Hz), 1.40-1.63 (4H, m), 2.18 (2H, t, J=7 Hz), 2.51-2.63 (2H, m),3.03 (2H, q, J=7 Hz), 3.47 (3H, s), 3.93 (2H, q, J=7 Hz), 4.12 (2H, q,J=7 Hz), 4.35 (1H, d, J=3 Hz), 4.63 (2H, s), 4.77 (1H, d, J=3 Hz), 5.92(1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.92 (1H, m), 8.53 (1H, d, J=2Hz), 8.93 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 466

EXAMPLE 241 Ethyl5-[7-ethyl-2-phenyl-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.15-1.31 (7H, m), 1.37 (3H, t, J=7 Hz), 1.87 (2H, t,J=7 Hz), 2.43 (2H, m), 3.01 (2H, q, J=7 Hz), 3.98 (2H, q, J=7 Hz), 5.45(1H, d, J=11 Hz), 5.88 (1H, d, J=18 Hz), 5.98 (1H, d, J=5 Hz), 6.62 (1H,d, J=5 Hz), 6.78 (1H, dd, J=11 and 18 Hz), 7.44-7.55 (5H, m), 7.81 (1H,m), 8.55 (1H, m), 8.72 (1H, m)

EXAMPLE 242

A solution of5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid (50 mg) in dioxane (15 mL) in a sealed tube was added 50%dimethylamine in water (15 mL). The mixture was heated at 175° C.overnight. The cooled reaction mixture was concentrated in vacuo. Theresidue was dissolved in water (1 mL) and the pH was adjusted to 7-8.The mixture was extracted with chloroform three times. The organic layerwas dried over magnesium sulfate and evaporated in vacuo. The residuewas purified by flash silica gel chromatography (silica gel, 50 mL)eluted with chloroform-ethyl acetate=1-1 and chloroform-methanol=20-1 togive yellow oil (43 mg). The oil was crystallized from isopropyl etherto give5-{4-[2-(dimethylamino)-4-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid as an yellow solid (27 mg, 52.8%).

5-{4-[2-(Dimethylamino)-4-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

NMR (CDCl₃, δ): 1.36 (3H, t, J=8 Hz), 1.40-1.65 (4H, m), 2.25 (2H, t,J=8 Hz), 1.86-1.96 (2H, m), 2.55 (3H, s), 3.00 (2H, q, J=8 Hz), 4.08(2H, q, J=8 Hz), 5.54 (1H, d, J=10 Hz), 5.86 (1H, d, J=5 Hz), 6.25 (1H,d, J=16 Hz), 6.51 (1H, d, J=5 Hz), 6.87 (1H, dd, J=16, 10 Hz), 7.16 (1H,dd, J=6, 1 Hz), 7.33 (1H, br s), 8.70 (1H, d, J=6 Hz)

EXAMPLE 243

To a suspension of7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde(40 mg) in ethanol (1 mL) was added 2-aminoethanol (11.8 mg), sodiumcyanoborohydride (12.1 mg), and acetic acid (1 drop) in an ice-waterbath. After 10 minutes, the mixture was stirred at ambient temperature.After 2 hours, sodium cyanoborohydride (11.8 mg) was added and thereaction mixture was acidified to pH4 with acetic acid (5 drops). Afterstirring overnight, the reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with saturated sodiumbicarbonate, water, and brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by p-TLC(chloroform-methanol=10-1) to give2-({[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl}amino)ethanolas pale yellow oil (21 mg).

2-({[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl}amino)ethanol

NMR (CDCl₃, δ): 1.43 (6H, d, J=7 Hz), 2.65 (2H, t, J=7 Hz), 3.42 (1H,m), 353 (2H, t, J=7 Hz), 3.59 (2H, s), 6.01 (1H, d, J=5 Hz), 6.77 (1H,d, J=5 Hz), 7.14-7.24 (2H, m), 7.35-7.44 (2H, m)

MS (ESI⁺): m/z 362 (M+H)

EXAMPLE 244

To a solution of[4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methanol (505mg) and triethylamine (997 mg) in dichloromethane (4 mL) and dimethylsulfoxide (2 mL) was added sulfur trioxide pyridine complex (941 mg) inan ice-water bath under nitrogen. After 30 minutes, the mixture wasstirred at ambient temperature for 2 hours. The reaction mixture wasconcentrated to about ⅓ volume. The mixture was partitioned betweenethyl acetate and water. The organic layer was washed with water threetimes and brine, dried over magnesium sulfate, and evaporated in vacuo.The residue was purified by flash silica gel chromatography (silica gel,30 mL) eluted with hexane-chloroform=3-1 and 2-1 to give4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazine-3-carbaldehyde as anyelow solid (340 mg, 67.9%).

4-(4-Fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazine-3-carbaldehyde

NMR (CDCl₃, δ): 2.77 (3H, s), 6.50 (1H, m), 6.86 (1H, m), 7.20-7.30 (2H,m), 7.44-7.54 (2H, m), 8.89 (1H, br s), 9.79 (1H, s)

EXAMPLE 245

A mixture of ethyl4-(4-fluorophenyl)-2-isopropyl-7-vinylpyrrolo[1,2-b]pyridazine-3-carboxylate(8.9 g) and 10% palladium on carbon (900 mg) in ethanol (180 mL) wasstirred under hydrogen atomosphere (3.5 atm) at ambient temperature.After 10 hours, the mixture was stood overnight. To the mixture wasadded 10% palladium on carbon (900 mg) and was stirred under hydrogenatomosphere (35 atm) at ambient temperature. After 12 hours, the mixturewas stood overnight. To the mixture was added 10% palladium on carbon(900 mg) and was stirred under hydrogen atomosphere (35 atm) at ambienttemperature for 8 hours. The mixture was filtered through Celite. Thefiltrate was concentrated in vacuo to give ethyl7-ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylateas an yellow oil (9.0 g, 100.5%).

Ethyl7-ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (CDCl₃, δ): 0.96 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 3.05 (2H, q,J=8 Hz), 4.01 (2H, q, J=8 Hz), 6.27 (1H, d, J=5 Hz), 6.64 (1H, d, J=5Hz), 7.10-7.19 (2H, m), 7.41-7.49 (2H, m)

MS (ESI⁺): m/z 362 (M+H)

The following compounds were obtained in substantially the same manneras that of Example 245.

EXAMPLE 2465-[7-Ethyl-4-(5-ethyl-3-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid from5-[7-ethyl-2-methyl-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.30 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.45-1.65(4H, m), 2.22 (2H, m), 2.35-2.50 (2H, m), 2.56 (3H, s), 2.75 (2H, q, J=7Hz), 3.00 (2H, q, J=7 Hz), 5.84 (1H, d, J=4 Hz), 6.52 (1H, d, J=4 Hz),7.57 (1H, s), 8.42 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 366 (M+H), MS (ESI⁻): m/z 364

EXAMPLE 2475-[7-Ethyl-4-(5-ethyl-3-pyridinyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 130 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.45-1.64(4H, m), 2.17 (2H, m), 2.45-2.67 (2H, m), 2.73 (2H, q, J=7 Hz), 3.04(2H, q, J=7 Hz), 3.45 (3H, s), 4.62 (2H, m), 5.89 (1H, d, J=4 Hz), 6.58(1H, d, J=4 Hz), 7.59 (1H, s), 8.44 (1H, s), 8.54 (1H, s)

MS (ESI⁺): m/z 396

EXAMPLE 248 Ethyl5-[7-ethyl-4-(5-ethyl-3-pyridinyl)-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.04-1.23 (7H, m), 1.32 (3H, t, J=7 Hz), 1.37 (3H, t,J=7 Hz), 1.86 (2H, t, J=7 Hz), 2.42 (2H, m), 2.74 (2H, q, J=7 Hz), 3.01(2H, q, J=7 Hz), 3.99 (2H, q, J=7 Hz), 5.97 (1H, d, J=5 Hz), 6.62 (1H,d, J=5 Hz), 7.45-7.53 (5H, m), 7.60 (1H, m), 8.50 (1H, m), 8.56 (1H, m)

EXAMPLE 249

To a solution of3-(7-ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzamide (35 mg) inethanol (1 mL) was added water (0.2 mL) and potassium hydroxide (68.9mg) at ambient temperature. The reaction mixture was heated at 60° C.After 2 hours, potassium hydroxide (100 mg) was added. After 5 hours,potassium hydroxide (100 mg) was added. After 12 hours, the mixture wasacidified with 1N hydrogen chloride. The precipitate was filtered,washed with water and ethyl acetate to give3-(7-ethyl-2-neopentylpyrrolo-[1,2-b]pyridazin-4-yl)benzoic acid as anyellow solid (19 mg, 54.1%).

3-(7-Ethyl-2-neopentylpyrrolo[1,2-b]pyridazin-4-yl)benzoic acid

NMR (CDCl₃, δ): 1.05 (9H, s), 1.39 (3H, t, J=8 Hz), 2.69 (2H, s), 3.04(2H, q, J=8 Hz), 6.42 (1H, s), 6.54 (1H, d, J=5 Hz), 6.65 (1H, d, J=5Hz), 7.62 (1H, t, J=8 Hz), 7.97 (1H, d, J=8 Hz), 8.21 (1H, d, J=8 Hz),8.46 (1H, br s)

MS (ESI⁺): m/z 337 (M+H)

The following compound was obtained in substantially the same manner asthat of Example 249.

EXAMPLE 250 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoicacid

NMR (CDCl₃, δ): 1.44 (3H, t, J=8 Hz), 3.11 (2H, q, J=8 Hz), 6.56 (1H,m), 6.61 (1H, d, J=5 Hz), 6.72 (1H, d, J=5 Hz), 7.03 (1H, br s), 7.07(1H, d, J=5 Hz), 7.55-7.69 (2H, m), 8.03 (1H, br d, J=8 Hz), 8.23 (1H,br d, J=8 Hz), 8.52 (1H, br s)

EXAMPLE 251

A solution of ethyl5-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate(190 mg) in methanol (5 mL) and 1N hydrochloric acid (5 mL) was stirredat ambient temperature for 2 hours. The solution was diluted with brineand extracted with chloroform. The organic layer was separated, driedover magnesium sulfate, and evaporated in vacuo. The residue waspurified by silica gel column chromatography eluting with a mixture ofhexane and ethyl acetate (10:1-2:1) to give ethyl5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoateas an yellow oil (160 mg).

Ethyl5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.60(4H, m), 2.19 (2H, t, J=7 Hz), 2.36-2.47 (2H, m), 2.57 (3H, s), 2.70(3H, s), 3.02 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 5.81 (1H, d, J=4Hz), 6.53 (1H, d, J=4 Hz), 8.23 (1H, m), 8.78 (1H, d, J=2 Hz), 9.23 (1H,d, J=2 Hz)

MS: (m/z) 408 (M+H)

The following compound was obtained in substantially the same manner asthat of Example 251.

EXAMPLE 252 Ethyl5-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.59(4H, m), 2.17 (2H, t, J=7 Hz), 2.50-2.63 (2H, m), 2.70 (3H, s), 3.03(2H, q, J=7 Hz), 3.46 (3H, s), 4.12 (2H, q, J=7 Hz), 4.63 (2H, s), 5.86(1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 8.26 (1H, m), 8.79 (1H, d, J=2Hz), 9.24 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 438

EXAMPLE 253

To a solution of ethyl5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylthio)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate(139 mg) in tetrahydrofuran (4 mL) and water (1 mL) was added oxone (287mg) and the mixture was stirred at ambient temperature for 4 hours. Thesolution was diluted with water and extracted with ethyl acetate. Theorganic layer was separated, washed with saturated sodium bicarbonatesolution, sodium thiosulfate solution and brine, dried over magnesiumsulfate, and evaporated in vacuo. The residue was purified by silica gelcolumn chromatography eluting with a mixture of hexane and ethyl acetate(10:1-1:1) to give ethyl5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylsulfonyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoateas an yellow oil (124 mg).

Ethyl5-{4-(2-chloro-4-pyridinyl)-7-ethyl-2-[(methylsulfonyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

NMR (CDCl₃, δ): 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.63(4H, m), 2.21 (2H, t, J=7 Hz), 2.57-2.68 (2H, m), 3.02 (2H, q, J=7 Hz),3.12 (3H, s), 4.10 (2H, q, J=7 Hz), 4.53 (2H, s), 5.98 (1H, d, J=4 Hz),6.68 (1H, d, J=4 Hz), 7.27 (1H, m), 7.38 (1H, s), 8.56 (1H, d, J=5 Hz)

EXAMPLE 254

A mixture of ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate(167 mg) and copper(I) cyanide (37 mg) in 1-methyl-2-pyrrolidinone (3mL) was stirred at 170° C. for 4 hours. The mixture was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith water and brine, dried over magnesium sulfate, and evaporated invacuo. The residue was purified by silica gel column chromatographyeluting with a mixture of hexane and ethyl acetate (20:1-5:1) to giveethyl5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoateas an yellow oil (88 mg).

Ethyl5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 124 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.62(4H, m), 2.21 (2H, t, J=7 Hz), 2.35-2.47 (2H, m), 2.57 (3H, s), 3.02(2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.79 (1H, d, J=4 Hz), 6.54 (1H,d, J=4 Hz), 7.98 (1H, m), 8.80 (1H, d, J=2 Hz), 8.97 (1H, d, J=2 Hz)

MS (ESI⁺): m/z 391.

The following compounds were obtained in substantially the same manneras that of Example 254.

EXAMPLE 2555-[4-(5-Cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.40-1.67 (4H, m), 2.28 (2H, m),2.37-2.47 (2H, m), 2.57 (3H, s), 3.01 (2H, q, J=7 Hz), 5.80 (1H, d, J=4Hz), 6.55 (1H, d, J=4 Hz), 8.01 (1H, s), 8.81 (1H, br), 8.98 (1H, br)

EXAMPLE 256 Ethyl5-[4-(5-cyano-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60(4H, m), 2.19 (2H, t, J=7 Hz), 2.49-2.60 (2H, m), 3.04 (2H, q, J=7 Hz),3.46 (3H, s), 4.12 (2H, q, J=7 Hz), 4.63 (2H, s), 5.84 (1H, d, J=4 Hz),6.63 (1H, d, J=4 Hz), 8.02 (1H, m), 8.83 (1H, d, J=2 Hz), 8.98 (1H, d,J=2 Hz)

EXAMPLE 2575-[4-(5-Cyano-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.38 (3H, t, J=7 Hz), 1.40-1.65 (4H, m), 2.27 (2H, t,J=7 Hz), 2.48-2.64 (2H, m), 3.03 (2H, q, J=7 Hz), 3.46 (3H, s), 4.64(2H, s), 5.84 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 8.03 (1H, s), 8.82(1H, s), 8.97 (1H, s)

EXAMPLE 2585-[4-(5-Cyano-3-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

NMR (CDCl₃, δ): 1.06-1.24 (4H, m), 1.36 (3H, t, J=7 Hz), 1.94 (2H, t,J=7 Hz), 2.38 (2H, m), 2.99 (2H, q, J=7 Hz), 5.88 (1H, d, J=5 Hz), 6.64(1H, d, J=5 Hz), 7.44-7.52 (5H, m), 8.06 (1H, s), 8.87 (1H, s), 8.98(1H, s)

MS (ESI⁺): m/z 425 (M+H)

EXAMPLE 259

To a suspension of lithium aluminum hydride (98.8 mg) in tetrahydrofuran(10 mL) was added ethyl5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate(600 mg) in tetrahydrofuran (10 mL) under ice-water cooling and themixture was stirred at 0° C. for 2 hours. The reaction was quenched withsaturated potassium sodium tartrate solution and the insolubles werefiltereed off and washed with ethyl acetate. The filtrates were washedwith brine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by silica gel column chromatography eluting with amixture of hexane and ethyl acetate (10:1-2:1) to give5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanolas an yellow oil (478 mg).

5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol

NMR (CDCl₃, δ): 0.90-1.22 (6H, m), 1.27 (1H, t, J=7 Hz), 1.36 (3H, t,J=7 Hz), 2.37-2.47 (2H, m), 3.02 (2H, q, J=7 Hz), 3.29-3.41 (2H, m),5.97 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.32 (1H, m), 7.40-7.55 (8H,m)

EXAMPLE 260

To a solution of5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol(63.0 mg) and triethylamine (22.8 mg) in dichloromethane (3 mL) wasadded methanesulfonyl chloride (18.9 mg) under ice-water cooling and themixture was stirred at 0° C. for 1 hour. The solution was washed withbrine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was added to sodium cyanide (14.7 mg) in dimethylformamide (2mL) and the mixture was stirred at 60° C. for 5 hours. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with water and brine, dried over magnesium sulfate,and evaporated in vacuo. The residue was purified by silica gel columnchromatography eluting with a mixture of hexane and ethyl acetate(20:1-5:1) to give6-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]hexanenitrileas an yellow oil (585 mg).

6-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]hexanenitrile

NMR (CDCl₃, δ): 1.00-1.15 (4H, m), 1.17-1.28 (2H, m), 1.36 (3H, t, J=7Hz), 1.98 (2H, t, J=7 Hz), 2.38-2.47 (2H, m), 3.03 (2H, q, J=7 Hz), 5.99(1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.32 (1H, m), 7.38-7.56 (8H, m)

MS (ESI⁺): m/z 428

EXAMPLE 261

A mixture of5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol(65 mg), trimethyloxonium tetrafluoroborate (275 mg) and2,6-di-t-butyl-4-methylpyridine (47.8 mg) in 1,2-dichloroethane (3 mL)was stirred at ambient temperature for 4 hours. The solution was washedwith water, 1N hydrochloric acid, water, saturated sodium bicarbonatesolution and brine, dried over magnesium sulfate, and evaporated invacuo. The residue was purified by silica gel column chromatographyeluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give4-(3-chlorophenyl)-7-ethyl-3-(5-methoxypentyl)-2-phenylpyrrolo[1,2-b]pyridazineas an yellow oil (60 mg).

4-(3-chlorophenyl)-7-ethyl-3-(5-methoxypentyl)-2-phenylpyrrolo[1,2-b]pyridazine

NMR (CDCl₃, δ): 0.90-1.32 (6H, m), 1.36 (3H, t, J=7 Hz), 2.37-2.47 (2H,m), 3.03 (2H, q, J=7 Hz), 3.08 (2H, t, J=7 Hz), 3.31 (3H, s), 5.97 (1H,d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.27-7.33 (1H, m), 7.38-7.53 (8H, m)

MS (ESI⁺): m/z 433

EXAMPLE 262

To a solution of5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol(55 mg) and triethylamine (19.9 mg) in dichloromethane (3 mL) was addedmethanesulfonyl chloride (165 mg) under ice-water cooling and themixture was stirred at 0° C. for 1 hour. The solution was washed withbrine, dried over magnesium sulfate, and evaporated in vacuo. To theresidue in 1,2-dichloroethane (3 mL) was added 2 M dimethylamine intetrahydrofuran (3 mL) and the mixture was stirred at 60° C. for 120hours. The solution was diluted with chloroform, washed with brine,dried over magnesium sulfate, and evaporated in vacuo. The residue waspurified by silica gel column chromatography eluting with a mixture ofhexane and ethyl acetate (20:1-5:1) to give5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N,N-dimethyl-1-pentanamineas an yellow oil (38 mg).

N-{5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentyl}-N,N-dimethylamine

NMR (CDCl₃, δ): 0.86-0.97 (2H, m), 1.02-1.15 (4H, m), 1.36 (3H, t, J=7Hz), 1.97-2.04 (2H, m), 2.11 (6H, s), 2.37-2.47 (2H, m), 3.02 (2H, q,J=7 Hz), 5.97 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.31 (1H, m),7.39-7.54 (8H, m)

MS (ESI⁺): m/z 446

EXAMPLE 263

To a stirred solution of5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid (60 mg) in dichloromethane (2 ml) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (353 mg) and2-animopyridine (20 mg) and the reaction mixture was stirred for 10minutes. 4-Dimethylaminopyridine (2 mg) was added and the reactionmixture was stirred at room temperature for 15 hours. The mixture wasdiluted with water and extracted with ethyl acetate. The organic layerwas washed with water, brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel eluting with a mixture of ethyl acetate andn-hexane (1:2) to give5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanamide(55.7 mg) as an yellow amorphous.

5-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanamide

mp: 67-70° C.

NMR (CDCl3, δ): 1.12 (2H, quintet, J=7 Hz), 1.30 (2H, quintet, J=7 Hz),1.36 (3H, t, J=7 Hz), 1.95 (2H, t, J=7 Hz), 2.43 (2H, q, J=7 Hz), 3.02(2H, q, J=7 Hz), 5.90 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.00-7.05(1H, m), 7.43-7.54 (5H, m), 7.59-7.77 (6H, m), 8.11 (1H, d, J=75 Hz),8.24 (1H, d, J=4 Hz)

MS: (m/z) 499 (M+), 45 (bp)

The following compounds were obtained in substantially the same manneras that of Example 263.

EXAMPLE 2645-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanamide

NMR (CDCl₃, δ): 1.15 (2H, quintet, J=7 Hz), 1.24(2H, quintet, J=7 Hz),1.36(3H, t, J=7 Hz), 1.91(2H, t, J=7 Hz), 2.45(2H, t, J=7 Hz), 3.00(2H,q, J=7 Hz), 5.97(1H, d, J=5 Hz), 6.60(1H, d, J=4 Hz), 7.00(1H, t, J=7Hz), 7.30(1H, s), 7.38-7.53(7H, m), 7.65-7.73(2H, m), 8.11(1H, d, J=7Hz), 8.25(1H, d, J=5 Hz)

MS: (m/z) 509 (M⁺+H), 74 (bp)

EXAMPLE 265N-{5-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide

NMR (CDCl₃, δ): 1.08 (2H, quintet, J=7 Hz), 1.23 (2H, quintet, J=7 Hz),1.36 (3H, t, J=7 Hz), 1.85 (2H, t, J=7 Hz), 2.44 (2H, t, J=7 Hz), 3.02(2H, q, J=7 Hz), 3.21 (3H, s), 5.99 (1H, d, J=4 Hz), 6.62 (1H, d, J=4Hz), 7.30-7.33 (1H, m), 7.43-7.55 (8H, m)

EXAMPLE 2665-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-(2-pyridinyl)pentanamide

NMR (CDCl₃, δ): 1.12 (2H, quintet, J=7 Hz), 1.27 (2H, quintet, J=7 Hz),1.36 (3H, t, J=7 Hz), 1.97 (2H, t, J=7 Hz), 2.45 (2H, t, J=7 Hz), 3.01(2H, q, J=7 Hz), 5.95 (1H, d, J=5 Hz), 6.63 (1H, d, J=4 Hz), 7.01 (1H,t, J=7 Hz), 7.31 (1H, d, J=7 Hz), 7.41-7.53 (6H, m), 7.68 (1H, ddd, J=7,7, 1 Hz), 7.77 (1H, s), 8.12 (1H, d, J=75 Hz), 8.24 (1H, d, J=5 Hz),8.53 (1H, d, J=6 Hz)

MS: (m/z) 510 (M⁺+H), 80 (bp)

EXAMPLE 267N-{5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoyl}methanesulfonamide

mp: 124-125° C.

NMR (CDCl₃, δ): 1.37 (3H, t, J=7 Hz), 1.43-1.49 (2H, m), 1.55-1.65 (2H,m), 2.23 (2H, t, J=7 Hz), 2.34-2.48 (2H, m), 2.55 (3H, s), 3.01 (2H, q,J=7 Hz), 3.28 (3H, s), 5.87 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.09(1H, s), 7.40 (1H, s), 8.53 (1H, s), 8.77 (1H, s)

MS: (m/z) 493(M⁺), 491 (M⁺−2), 137 (bp)

EXAMPLE 268

To a solution of ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(100.0 mg) and (bromomethyl)benzene (111 mg) in N,N-dimethylformamide (1mL) was added 60% sodium hydride (17.4 mg) under an ice-bath. Afterstirring for 25 hour, the reaction was quenched by adding 1Nhydrochloric acid (1 mL), and the mixture was partitioend between ethylacetate (10 mL) and water (5 mL). The organic layer was washed with 1Nhydrochloric acid (5 mL), water (5 mL, three times), and brine, driedover magnesium sulfate, and evaporated. Flash silica gel columnchromatography eluting with ethyl acetate-hexane=1/40 to 20/40 affordedethyl5-[2-[(benzyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoateas an yellow gum (47.7 mg, 39.9%).

Ethyl5-[2-[(benzyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.34-1.48 (5H, m), 2.09 (2H, m),2.53 (2H, m), 3.04 (2H, q, J=7 Hz), 4.07 (2H, J=7 Hz), 4.65 (2H, s),4.72 (2H, s), 5.90 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.29-7.38 (5H,m), 7.86 (1H, s), 8.54 (1H, m), 8.77 (1H, m)

The following compound was obtained in substantially the same manner asthat of Example 268.

EXAMPLE 269 Ethyl5-(4-(5-bromo-3-pyridinyl)-2-{[(4-cyanobenzyl)oxy]methyl}-7-ethylpyrrolo[1,2-b]pyridazin-3-yl)pentanoate

NMR (CDCl₃, δ): 1.23 (3H, J=7 Hz), 1.35-1.55 (7H, m), 2.12 (2H, t, J=7Hz), 2.57 (2H, m), 3.02 (2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 4.49 (2H,s), 4.76 (2H, s), 5.93 (1H, d, J=7 Hz), 6.62 (1H, d, J=7 Hz), 7.48 (2H,d, J=8 Hz), 7.65 (2H, d, J=8 Hz), 7.86 (1H, m), 8.54 (1H, m), 8.78 (1H,m)

EXAMPLE 270

To a solution of ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(200 mg) and triethylamine (65.9 mg) in dichloromethane (2 mL) was addedmethanesulfonyl chloride (54.7 mg) under an ice-bath. After stirring for1 hour, the reaction was quenched by adding 1N hydrochloric acid (1 mL).The mixrure was partitioned between ethyl acetate (20 mL) and 1Nhydrochloric acid (5 mL). The organic layer was washed with saturatedsodium bicarbonate and brine, dried over magnesium sulfate, andevaporated to give ethyl5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(methylsulfonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoateas an yellow gum (247 mg).

Ethyl5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(methylsulfonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

NMR (CDCl₃, δ): 1.22 (3H, t, J=7 Hz), 1.34-1.65 (7H, m), 2.20 (2H, t,J=7 Hz), 2.55 (2H, m), 3.02 (2H, q, J=7 Hz), 3.15 (3H, s), 4.07 (2H, q,J=7 Hz), 5.42 (2H, s), 5.99 (1H, d, J=5 Hz), 6.68 (1H, d, J=5 Hz), 7.87(1H, m), 8.54 (1H, m), 8.81 (1H, m)

EXAMPLE 271

A mixture of ethyl5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(methylsulfonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate(50.0 mg), benzylamine (29.8 mg) in dichloromathane (1 mL) was stirredfor 20 hour at room temperature. The mixture was partitioned betweenethyl acetate and water. The organic layer was washed with brine, dried,and evaporated. Preparative thin layer chromatography eluting with ethylacetate-hexane=1:2 afforded ethyl5-[2-[(benzylamino)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoateas an yellow gum (19.1 mg).

Ethyl5-[2-[(benzylamino)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.30-1.50 (7H, m), 2.13 (2H, t,J=7 Hz), 2.42 (2H, m), 3.03 (2H, q, J=7 Hz), 3.96 (4H, m), 4.09 (2H, q,J=7 Hz), 5.89 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.23-7.42 (5H, m),7.86 (1H, m), 8.53 (1H, m), 8.77 (1H, m)

The following compound was obtained in substantially the same manner asthat of Example 271.

EXAMPLE 272 Ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

NMR (CDCl₃, δ): 1.23 (3H, t, J=7 Hz), 1.31-1.56 (7H, m), 2.19 (2H, t,J=7 Hz), 2.45-2.65 (6H, m), 3.02 (2H, q, J=7 Hz), 3.60-3.75 (6H, m),4.09 (2H, q, J=7 Hz), 5.88 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.89(1H, m), 8.55 (1H, m), 8.78 (1H, m)

EXAMPLE 273

To a solution of(7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl)methanol(40 mg) in N,N-dimethylformamide (1 mL) was added 40% sodium hydride inoil (55 mg) in an ice-water bath. After 20 minutes, to the mixture wasadded 2-bromoethyl acetate (31 mg) at the temperature. After 15 minutes,the reaction mixture was stirred at ambient temperature for 5 hours. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with water three times and brine, dried overmagnesium sulfate, and evaporated in vacuo. The residue was purified byp-TLC (hexane-ethyl acetate=10-1) to give[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methylacetate as a pale yellow solid (42 mg).

[7-Chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methylacetate

NMR (CDCl₃, δ): 1.41 (6H, d, J=8 Hz), 2.06 (3H, s), 3.21 (1H, m), 4.92(2H, s), 6.14 (1H, d, J=5 Hz), 6.72 (1H, d, J=5 Hz), 7.13-7.24 (2H, m),7.34-7.43 (2H, m)

MS (ESI⁺): m/z 361 (M+H)

The following compound was obtained in substantially the same manner asthat of Preparation 20.

EXAMPLE 274Ethyl{[7-ethyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methoxy}acetate

NMR (CDCl₃, δ): 1.25 (3H, t, J=8 Hz), 1.30-1.45 (9H, m), 3.04 (2H, q,J=8 Hz), 3.51 (1H, m), 3.97 (2H, s), 4.15 (2H, q, J=8 Hz), 4.40 (2H, s),6.06 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz), 7.11-7.22 (2H, m), 7.41-7.51(2H, m)

MS (ESI⁺): m/z 399 (M+H)

The following compound was obtained in substantially the same manner asthat of Preparation 276.

EXAMPLE 275 Ethyl2-(2-amino-2-oxoethyl)-4-(4-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate

NMR (CDCl₃, δ): 0.84 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 3.06 (2H, q,J=7 Hz), 3.96 (2H, q, J=7 Hz), 4.02 (3H, s), 5.41 (1H, s, br), 6.09 (1H,s, br), 6.28 (1H, d, J=5 Hz), 6.75 (1H, d, J=5 Hz), 7.53 (2H, d, J=9Hz), 7.77 (2H, d, J=9 Hz)

MS (ESI⁺): m/z 753 (2M+H)

EXAMPLE 276

A mixture of4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylicacid (40.0 mg), pyrrolidine (10.8 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.1 mg),and 1-hydroxybenzotriazole (21.9 mg) in N,N-dimethylformamide (1 mL) wasstirred for 6 hour at room temperature. The mixture was partitionedbetween ethyl acetate (20 mL) and 1N hydrochloric acid (10 mL). Theorganic layer was washed with water (10 mL) three times, saturatedsodium bicarbonate (10 mL), and brine, dried, and evaporated to give3-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinylcarbonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrileas an yellow solid (35.6 mg).

3-[7-Ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinylcarbonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

NMR (CDCl₃, δ): 1.38 (2H, m), 1.99 (4H, m), 3.07 (2H, q, J=7 Hz), 3.23(3H, s), 3.59 (2H, t, J=7 Hz), 3.68 (2H, t, J=7 Hz), 6.27 (1H, d, J=5Hz), 6.83 (1H, d, J=5 Hz), 7.57-7.66 (3H, m), 7.79 (1H, m)

MS (ESI⁺): m/z 423 (M+H)

EXAMPLE 277

To a solution of3-[7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoic acid (40 mg)in N,N-dimethylformamide (4 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg),1-hydroxybenzotriazole (24 mg), and 2-aminoethanol (15 mg) at ambienttemperature. After stirring overnight, the reaction mixture waspartitioned between ethyl acetate and saturated sodium bicarbonate. Theorganic layer was washed with water 3 times and brine, dried overmagnesium sulfate, and evaporated in vacuo. The residue was purified byflash silica gel column chromatography (silica gel, 40 mL) eluted withchlorofomm-methanol=50-1 and 20-1 to give an yellow solid (42 mg). Thesolid was triturated with isopropyl ether to give3-[7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]-N-(2-hydroxyethyl)benzamideas an yellow solid (35 mg).

3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]-N-(2-hydroxyethyl)benzamide

NMR (CDCl₃, δ): 1.43 (3H, t, J=8 Hz), 2.39-2.49 (2H, m), 3.10 (2H, q,J=8 Hz), 3.60-3.74 (2H, m), 3.80-3.94 (2H, m), 6.53-6.86 (4H, m), 7.00(1H, s), 6.61 (1H, d, J=5 Hz), 6.72 (1H, d, J=5 Hz), 7.03 (1H, br s),7.07 (1H, d, J=5 Hz), 7.55-7.65 (2H, m), 7.86-7.97 (2H, m), 8.17 (1H, brs)

MS (ESI⁺): m/z 376 (M+H)

The following compounds were obtained in substantially the same manneras that of Example 283.

EXAMPLE 2785-[4-(3-Cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-methylpentanamide

mp: 60° C.

NMR (CDCl₃, δ): 1.02-1.12 (2H, m), 1.17-1.25 (2H, m), 1.36 (3H, t, J=7Hz), 1.73 (2H, t, J=7 Hz), 2.40(2H, t, J=7 Hz), 2.71 (3H, d, J=7 Hz),3.03 (2H, q, J=7 Hz), 5.09 (1H, broad s), 5.90 (1H, d, J=4 Hz), 6.63 1H,d, J=4 Hz), 7.45-7.55 (5H, m), 7.60-7.78 (4H, m)

MS: (m/z) 437 (M⁺+H), 115 (bp)

EXAMPLE 2794-(3-Chlorophenyl)-7-ethyl-3-[5-(4-morpholinyl)-5-oxopentyl]-2-phenylpyrrolo[1,2-b]pyridazine

mp: 55-58° C.

NMR (CDCl3, δ): 1.05-1.14 (2H, m), 1.17-1.23 (2H, m), 1.35 (3H, t, J=7Hz), 1.84 (2H, t, J=7 Hz), 2.45 (2H, t, J=7 Hz), 3.02 (2H, q, J=7 Hz),3.24 (2H, t, J=6 Hz), 3.50 (2H, t, J=6 Hz), 3.55-3.62 (4H, m), 5.99 (1H,d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.30-7.35 (1H, m), 7.40-7.55 (8H, m)

MS: (m/z) 502 (M⁺+H), 115 (bp)

EXAMPLE 2805-[4-(3-Chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-methylpentanamide

mp: 70-72° C.

NMR (CDCl₃, δ): 1.06 (2H, quintet, J=7 Hz), 1.22 (2H, quintet, J=7 Hz),1.36 (3H, t, J=7 Hz), 1.72 (2H, t, J=7 Hz), 2.43 (2H, t, J=7 Hz), 2.70(3H, d, J=7 Hz), 3.03 (2H, q, J=7 Hz), 5.08 (1H, broad s), 5.99 (1H, d,J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.29-7.33 (1H, m), 7.41-7.55 (8H, m)

MS: (m/z) 446 (M⁺+H), 115 (bp)

EXAMPLE 2815-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N-methylpentanamide

NMR (CDCl₃, δ): 1.07 (2H, quintet, J=7 Hz), 1.23 (2H, quintet, J=7 Hz),1.36(3H, t, J=7 Hz), 1.74 (2H, t, J=7 Hz), 2.41 (2H, t, J=7 Hz), 2.71(3H, d, J=7 Hz), 3.02 (2H, q, J=7 Hz), 5.10 (1H, broad s), 5.95 (1H, d,J=4 Hz), 6.64 (1H, d, J=4 Hz), 7.31 (1H, d, J=7 Hz), 7.42 (1H, s),7.46-7.52 (1H, m), 7.41-7.55 (1H, d, J=7 Hz)

MS: (m/z) 447 (M⁺+H), 115 (bp)

EXAMPLE 2823-{7-Ethyl-3-[5-(4-morpholinyl)-5-oxopentyl]-2-phenylpyrrolo[1,2-b]pyridazin-4-yl}benzonitrilefrom5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

mp: 66-69° C.

NMR (CDCl3, δ): 1.04-1.12 (2H, m), 1.17-1.23 (2H, m), 1.36 (3H, t, J=7Hz), 1.84 (2H, t, J=7 Hz), 2.42 (2H, t, J=7 Hz), 3.03 (2H, q, J=7 Hz),3.23 (2H, t, J=6 Hz), 3.50 (2H, t, J=6 Hz), 3.55-3.63 (4H, m), 5.90 (1H,d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.43-7.55 (5H, m), 7.60-7.78 (4H, m)

MS: (m/z) 493 (M⁺+H), 126 (bp)

EXAMPLE 283

To a solution of5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid (50 mg) in N,N-dimethylformamide (1 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35 mg) and1-hydroxybenzotriazole (28 mg) at ambient temperature. After 30 minutes,to the mixture was added morpholine (24 mg). After 5 hours, the reactionmixture was partitioned between ethyl acetate and saturated sodiumbicarbonate. The organic layer was washed with water three times andbrine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by flash silica gel column chromatography (silicagel, 40 mL) eluted with hexane-ethyl acetate=3-1, 2-1, 1-1, 1-3, and 0-1to give3-{7-ethyl-2-methyl-3-[5-(4-morpholinyl)-5-oxopentyl]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrileas an yellow gum (53 mg).

3-{7-Ethyl-2-methyl-3-[5-(4-morpholinyl)-5-oxopentyl]pyrrolo[1,2-b]pyridazin-4-yl}benzonitrile

NMR (CDCl₃, δ): 1.15-1.61 (7H, m), 2.18 (2H, t, J=8 Hz), 2.41 (2H, t,J=8 Hz), 2.56 (3H, s), 3.00 (2H, q, J=8 Hz), 3.82 (2H, t, J=5 Hz),3.51-3.68 (6H, m), 5.78 (1H, d, J=5 Hz), 6.50 (1H, d, J=5 Hz), 7.56-7.67(3H, m), 7.74 (1H, m)

MS (ESI⁺): m/z 431 (M+H)

The following compound was obtained in substantially the same manner asthat of Example 283.

EXAMPLE 2845-[4-(3-Cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanamide

NMR (CDCl₃, δ): 1.31-1.61 (7H, m), 2.11 (2H, t, J=8 Hz), 2.40 (2H, t,J=8 Hz), 2.56 (3H, s), 3.00 (2H, q, J=8 Hz), 5.36 (2H, br s), 5.79 (1H,d, J=5 Hz), 6.50 (1H, d, J=5 Hz), 7.56-7.67 (3H, m), 7.75 (1H, m)

MS (ESI⁺): m/z 361 (M+H)

Preparation 178

To a suspension of 60% sodium hydride (8.79 g) in tetrahydrofuran (500mL) was addded cyclohexanol (10 g) and the mixture was stirred at 0° C.for 0.5 hour. To the mixture was added bromoacetic acid (13.9 g) underice-water cooling and the mixture was heated under reflux for 2 hours.After adding water to the mixture and organic solvent was evaporated invacuo. The aqueous solution was diluted with water, washed with ether,acidified with 1 N hydrochloric acid, and extracted with ether. Theorganic layer was separated, dried over magnesium sulfate, andevaporated in vacuo to give (cyclohexyloxy)acetic acid as colorless oil(133 g).

(cyclohexyloxy)acetic acid

¹H NMR (CDCl₃) δ 1.18-1.47 (5H, m), 1.52-1.63 (1H, m), 1.72-1.85 (2H,m), 1.90-2.03 (2H, m), 3.36-3.47 (1H, m), 4.13 (2H, s).

The following compound(s) was (were) obtained in substantially the samemanner as that of Preparation 178.

Preparation 179

Isopropoxyacetic Acid

¹H NMR (CDCl₃) δ 1.24 (6H, d, J=7 Hz), 3.68-3.82 (1H, m), 4.11 (2H, s).

The following compound(s) was (were) obtained in substantially the samemanner as that of Preparation 129 and Preparation 130.

Preparation 180

tert-butyl 4-(benzyloxy)-3-oxobutanoate

¹H NMR (CDCl₃) δ 1.44 (9H, s), 3.45 (2H, s), 4.14 (2H, s), 4.60 (2H, s),7.28-7.40 (5H, m).

Preparation 181

tert-butyl 4-(cyclohexyloxy)-3-oxobutanoate

¹H NMR (CDCl₃) δ 1.18-1.43 (5H, m), 1.47 (9H, s), 1.53-1.63 (1H, m),1.69-1.85 (2H, m), 1.87-1.97 (2H, m), 3.24-3.38 (1H, m), 3.46 (2H, s),4.11 (2H, s).

Preparation 182

tert-butyl 4-isopropoxy-3-oxobutanoate

¹H NMR (CDCl₃) δ 1.20 (6H, d, J=7 Hz), 1.47 (9H, s), 3.45 (2H, s),3.60-3.70 (1H, m), 4.08 (2H, s).

The following compound(s) was (were) obtained in substantially the samemanner as that of Preparation 159.

Preparation 183

1-tert-butyl 4-ethyl 2-acetylsuccinate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.47 (9H, s), 2.35 (3H, s), 3.08(2H, m), 3.93 (1H, m), 4.12 (2H, q, J=7 Hz).

Preparation 184

1-tert-butyl 7-ethyl 2-[(benzyloxy)acetyl]heptanedioate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.30-1.50 (2H, m), 1.40 (9H, s),1.56-1.72 (2H, m), 1.75-1.95 (2H, m), 2.28 (2H, t, J=7 Hz), 3.52 (1H, t,J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.16 (2H, s), 4.59 (2H, s), 7.27-7.40(5H, m).

Preparation 185

1-tert-butyl 5-ethyl 2-[(benzyloxy)acetyl]pentanedioate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.41 (9H, s), 2.10-2.23 (2H, m),2.36 (2H, t, J=7 Hz), 3.66 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.18(2H, s), 4.60 (2H, s), 7.26-7.38 (5H, m).

Preparation 186

1-tert-butyl 7-ethyl 2-[(cyclohexyloxy)acetyl]heptanedioate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.44 (9H, s), 1.15-1.92 (16H, m),2.29 (2H, t, J=7 Hz), 3.24-3.38 (1H, m), 3.56 (1H, t, J=7 Hz), 4.12 (4H,m),

Preparation 187

1-tert-butyl 7-ethyl 2-(isopropoxyacetyl)heptanedioate

¹H NMR (CDCl₃) δ 1.20 (6H, d, J=7 Hz), 1.25 (3H, t, J=7 Hz), 1.25-1.45(2H, m), 1.45 (9H, s), 1.60-1.72 (2H, m), 1.75-1.95 (2H, m), 2.29 (2H,t, J=7 Hz), 3.54 (1H, t, J=7 Hz), 3.60-3.68 (1H, m), 4.11 (2H, s), 4.12(2H, q, J=7 Hz).

MS (ESI⁺): m/z 345.

The following compound(s) was (were) obtained in substantially the samemanner as that of Preparation 20.

Preparation 188

1-tert-butyl 5-ethyl 2-[(cyclohexyloxy)acetyl]pentanedioate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.45 (9H, s), 1.18-1.62 (6H, m),1.66-1.78 (2H, m), 1.84-1.98 (2H, m), 2.10-2.23 (2H, m), 2.38 (2H, t,J=7 Hz), 3.25-3.38 (1H, m), 3.69 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz),4.15 (2H, s).

MS (ESI⁺): m/z 357.

Preparation 189

To a suspension of 60% sodium hydride (527 mg) in dimethylformamide (20mL) was added 3,5-pyridinedicarboxylic acid (2.00 g) under ice-watercooling and the mixture was stirred at 0° C. for 1 hour. To the mixturewas added (bromomethyl)benzene (2.05 g) and the mixture was stirred at60° C. for 2 hours. The mixture was partitioned between ethyl acetateand water. The organic layer was washed with water and brine, dried overmagnesium sulfate, and evaporated in vacuo. The residue was trituratedwith ethyl acetate to give 5-[(benzyloxy)carbonyl]nicotinic acid as apale yellow powder (722 mg).

5-[(benzyloxy)carbonyl]nicotinic acid

¹H NMR (DMSO-d₆) δ 5.42 (2H, s), 7.34-7.54 (5H, m), 8.63 (1H, m),9.23-9.34 (2H, m).

The following compound(s) was (were) obtained in substantially the samemanner as that of Preparation 24.

Preparation 190

1-tert-butyl 4-ethyl2-acetyl-2-[(5-methyl-3-pyridinyl)carbonyl]succinate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.40 (9H, s), 2.38 (3H, s), 2.45(3H, s), 3.20 (2H, m), 4.13 (2H, q, J=7 Hz), 7.88 (1H, s), 8.57 (1H, s),8.74 (1H, s).

MS (ESI⁺): m/z 363.

Preparation 191

ethyl 2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate

¹H NMR (CDCl₃) δ 0.96 (3H, t, J=7 Hz), 2.15 (3H, s), 2.45 (3H, s), 4.03(2H, q, J=7 Hz), 4.12 (1H, t, J=7 Hz), 7.89 (1H, s), 8.54 (1H, s), 8.72(1H, s).

MS (ESI⁺): m/z 250.

Preparation 192

1-tert-butyl 6-ethyl2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]hexanedioate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.36 (9H, s), 1.60-1.73(2H, m),2.23-2.35 (2H, m), 2.38 (2H, t, J=7 Hz), 2.48 (3H, s), 4.12 (2H, q, J=7Hz), 8.20 (1H, m), 8.78 (1H, m), 8.81 (1H, m).

Preparation 193

1-tert-butyl 5-ethyl2-[(5-bromo-3-pyridinyl)carbonyl]-2-(methoxyacetyl)pentanedioate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.39 (9H, s), 2.40-2.47 (2H, m),2.55-2.67 (2H, m), 3.36 (3H, s), 4.12 (2H, q, J=7 Hz), 4.27 (1H, d, J=17Hz), 4.40 (1H, d, J=17 Hz), 8.21 (1H, m), 8.79 (1H, d, J=2 Hz), 8.82(1H, d, J=2 Hz).

MS (ESI⁺): m/z 472 474.

Preparation 194

1-tert-butyl 7-ethyl2-acetyl-2-({5-[(benzyloxy)carbonyl]-3-pyridinyl}carbonyl)heptanedioate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.20-1.40 (2H, m), 1.32 (9H, s),1.65-1.76 (2H, m), 2.19-2.26 (2H, m), 2.32 (2H, t, J=7 Hz), 2.44 (3H,s), 4.12 (2H, q, J=7 Hz), 5.41 (2H, s), 7.35-7.48 (5H, m), 8.62 (1H, m),9.07 (1H, d, J=2 Hz), 933 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 526.

Preparation 195

1-tert-butyl 7-ethyl2-[(benzyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.20-1.46 (2H, m), 1.32 (9H, s),1.60-1.74 (2H, m), 2.10-2.36 (4H, m), 2.35 (3H, s), 4.10 (2H, q, J=7Hz), 4.38 (1H, d, J=18 Hz), 4.53 (1H, d, J=18 Hz), 4.54 (2H, m),7.27-7.40 (5H, m), 7.79 (1H, m), 8.54 (1H, d, J=2 Hz), 8.72 (1H, d, J=2Hz).

MS (ESI⁺): m/z 512.

Preparation 196

1-tert-butyl 5-ethyl2-[(benzyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.34 (9H, s), 2.35 (3H, s),2.40-2.72 (4H, m), 4.12 (2H, q, J=7 Hz), 4.38 (1H, d, J=17 Hz), 4.50(1H, d, J=17 Hz), 4.53 (2H, m), 7.25-7.38 (5H, m), 7.81 (1H, s), 8.54(1H, s), 8.73 (1H, s).

MS (ESI⁺): m/z 484.

Preparation 197

1-tert-butyl 7-ethyl2-[(cyclohexyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.16-1.55 (10H, m), 1.37 (9H, s),1.60-1.76 (2H, m), 1.78-1.90 (2H, m), 2.15-2.28 (2H, m), 2.31 (2H, t,J=7 Hz), 2.39 (3H, s), 3.17-3.29 (1H, m), 4.12 (2H, q, J=7 Hz), 4.34(1H, d, J=18 Hz), 4.44 (1H, d, J=18 Hz), 7.86 (1H, s), 8.56 (1H, s),8.76 (1H, s).

MS (ESI⁺): m/z 504.

Preparation 198

1-tert-butyl 7-ethyl2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(cyclohexyloxy)acetyl]heptanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.39 (9H, s), 1.16-1.88 (14H, m),2.15-2.40 (4H, m), 3.16-3.28 (1H, m), 4.10 (2H, q, J=7 Hz), 4.28 (1H, d,J=18 Hz), 4.38 (1H, d, J=18 Hz), 8.20 (1H, m), 8.78 (1H, d, J=2 Hz),8.84 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 568 570.

Preparation 199

1-tert-butyl 5-ethyl2-[(cyclohexyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.15-1.38 (4H, m), 1.39 (9H, s),1.45-1.75 (4H, m), 1.76-1.93 (2H, m), 2.39 (3H, s), 2.45-2.75 (4H, m),3.17-3.30 (1H, m), 4.12 (2H, q, J=7 Hz), 4.32 (1H, d, J=17 Hz), 4.41(1H, d, J=17 Hz), 7.88 (1H, s), 8.55 (1H, s), 8.77 (1H, s).

MS (ESI⁺): m/z 476.

Preparation 200

1-tert-butyl 5-ethyl2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(cyclohexyloxy)acetyl]pentanedioate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.15-1.35 (4H, m), 1.40 (9H, s),1.40-1.65 (2H, m), 1.65-1.75 (2H, m), 1.75-1.92 (2H, m), 2.35-2.85 (4H,m), 3.16-3.32 (1H, m), 4.12 (2H, q, J=7 Hz), 4.28 (1H, d, J=17 Hz), 4.35(1H, d, J=17 Hz), 8.22 (1H, t, J=2 Hz), 8.78 (1H, d, J=2 Hz), 8.87 (1H,d, J=2 Hz).

MS (ESI⁺): m/z 540 542.

Preparation 201

1-tert-butyl 7-ethyl2-(isopropoxyacetyl)-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate

¹H NMR (CDCl₃) δ 1.12 (6H, d, J=7 Hz), 1.23 (3H, t, J=7 Hz), 1.30-1.55(2H, m), 1.37 (9H, s), 1.63-1.77 (2H, m), 2.19-2.28 (2H, m), 2.28 (2H,t, J=7 Hz), 2.39 (3H, s), 3.53-3.64 (1H, m), 4.10 (2H, q, J=7 Hz), 4.31(1H, d, J=18 Hz), 4.42 (1H, d, J=18 Hz), 7.86 (1H, s), 8.55 (1H, s),8.74 (1H, s).

MS (ESI⁺): m/z 464.

Preparation 202

1-tert-butyl 7-ethyl2-[(5-bromo-3-pyridinyl)carbonyl]-2-(isopropoxyacetyl)heptanedioate

¹H NMR (CDCl₃) δ 1.10 (6H, d, J=7 Hz), 1.24 (3H, t, J=7 Hz), 1.39 (9H,s), 1.18-1.48 (2H, m), 1.64-1.77 (2H, m), 2.18-2.37 (4H, m), 3.52-3.64(1H, m), 4.12 (2H, q, J=7 Hz), 4.25 (1H, d, J=17 Hz), 4.36 (1H, d, J=17Hz), 8.19 (1H, t, J=2 Hz), 8.77 (1H, d, J=2 Hz), 8.83 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 528 530.

Preparation 203

1-tert-butyl 7-ethyl2-[(acetyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]heptanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.33 (9H, s), 1.20-1.42 (2H, m),1.63-1.74 (2H, m), 2.14 (3H, s), 2.27-2.38 (4H, m), 2.40 (3H, s), 4.10(2H, q, J=7 Hz), 5.08 (1H, d, J=18 Hz), 5.36 (1H, d, J=18 Hz), 7.84 (1H,s), 8.56 (1H, s), 8.75 (1H, s).

MS (ESI⁺): m/z 464.

The following compound(s) was (were) obtained in substantially the samemanner as that of Preparation 78.

Preparation 204

ethyl 3-[(5-methyl-3-pyridinyl)carbonyl]-4-oxopentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 2.21 (3H, s), 2.44 (3H, s), 3.03(2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.96 (1H, t, J=7 Hz), 8.08 (1H,s), 8.66 (1H, s), 9.03 (1H, s).

MS (ESI⁺): m/z 264.

Preparation 205

ethyl 5-[(5-bromo-3-pyridinyl)carbonyl]-6-oxoheptanoate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.60-1.78 (2H, m), 1.98-2.12 (2H,m), 2.20 (3H, s), 2.36 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.39 (1H,t, J=7 Hz), 8.38 (1H, m), 8.87 (1H, d, J=2 Hz), 9.08 (1H, d, J=2 Hz).

Preparation 206

ethyl 4-[(5-bromo-3-pyridinyl)carbonyl]-6-methoxy-5-oxohexanoate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 2.04-2.16 (1H, m), 2.20-2.34 (1H,m), 2.40-2.48 (2H, m), 3.22 (3H, s), 3.93 (1H, d, J=17 Hz), 4.00 (1H, d,J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.85 (1H, m), 8.47 (1H, m), 8.88 (1H,s), 9.16 (1H, s).

MS (ESI⁺): m/z 372 374.

Preparation 207

benzyl 5-(2-acetyl-7-ethoxy-7-oxoheptanoyl)nicotinate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.65-1.75 (2H,m), 1.93-2.15 (2H, m), 2.19 (3H, s), 2.29 (2H, t, J=7 Hz), 4.12 (2H, q,J=7 Hz), 4.44 (1H, t, J=7 Hz), 5.43 (2H, s), 7.35-7.50 (5H, m), 8.81(1H, m), 9.28 (1H, d, J=2 Hz), 939 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 426.

Preparation 208

ethyl 8-(benzyloxy)-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.30-1.43 (2H, m), 1.60-1.69 (2H,m), 1.73-1.86 (1H, m), 1.95-2.08 (1H, m), 2.25 (2H, t, J=7 Hz), 2.34(3H, s), 4.05 (2H, s), 4.07 (2H, q, J=7 Hz), 4.35-4.45 (2H, m), 4.69(1H, t, J=7 Hz), 7.09 (2H, m), 7.17-7.25 (3H, m), 7.93 (1H, s), 8.58(1H, d, J=2 Hz), 8.94 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 412.

Preparation 209

ethyl 6-(benzyloxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 2.07-2.35 (2H, m), 2.34 (3H, s),2.38-2.48 (2H, m), 4.05 (2H, s), 4.12 (2H, q, J=7 Hz), 4.34 (1H, d, J=17Hz), 4.41 (1H, d, J=17 Hz), 4.90 (1H, m), 7.03 (2H, m), 7.15-7.25 (3H,m), 8.00 (1H, s), 8.57 (1H, s), 9.02 (1H, s).

MS (ESI⁺): m/z 384.

Preparation 210

ethyl8-(cyclohexyloxy)-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate

¹H NMR (CDCl₃) δ 0.91-1.70 (12H, m), 1.23 (3H, t, J=7 Hz), 1.70-1.85(2H, m), 1.96-2.04 (2H, m), 2.27 (2H, t, J=7 Hz), 2.43 (3H, s),3.14-3.28 (1H, m), 4.00 (2H, s), 4.12 (2H, q, J=7 Hz), 4.76 (1H, t, J=7Hz), 8.04 (1H, s), 8.62 (1H, s), 9.00 (1H, s).

MS (ESI⁺): m/z 404.

Preparation 211

ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-8-(cyclohexyloxy)-7-oxooctanoate

¹H NMR (CDCl₃) δ 0.95-1.87 (14H, m), 1.23 (3H, t, J=7 Hz), 1.96-2.07(2H, m), 2.28 (2H, t, J=7 Hz), 3.16-3.27 (1H, m), 3.96-4.07 (2H, m),4.12 (2H, q, J=7 Hz), 4.72 (1H, t, J=7 Hz), 8.38 (1H, m), 8.87 (1H, d,J=2 Hz), 9.08 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 468 470.

Preparation 212

ethyl6-(cyclohexyloxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

¹H NMR (CDCl₃) δ 0.88-1.25 (5H, m), 1.24 (3H, t, J=7 Hz), 1.40-1.83 (5H,m), 2.04-2.14 (1H, m), 2.18-2.34 (1H, m), 2.42 (2H, m), 2.44 (3H, s),3.13-3.27 (1H, m), 4.00 (2H, s), 4.12 (2H, q, J=7 Hz), 4.93 (1H, m),8.13 (1H, s), 8.63 (1H, d, J=2 Hz), 9.07 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 376.

Preparation 213

ethyl 4-[(5-bromo-3-pyridinyl)carbonyl]-6-(cyclohexyloxy)-5-oxohexanoate

¹H NMR (CDCl₃) δ 0.88-1.85 (10H, m), 1.25 (3H, t, J=7 Hz), 2.02-2.14(1H, m), 2.18-2.34 (1H, m), 2.40-2.50 (2H, m), 3.15-3.27 (1H, m), 3.97(1H, d, J=17 Hz), 4.02 (1H, d, J=17 Hz), 4.13 (2H, q, J=7 Hz), 4.87-4.95(1H, m), 8.48 (1H, t, J=2 Hz), 8.88 (1H, d, J=2 Hz), 9.19 (1H, d, J=2Hz).

MS (ESI⁺): m/z 440 442.

Preparation 214

ethyl 8-isopropoxy-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate

¹H NMR (CDCl₃) δ 0.86 (3H, d, J=7 Hz), 1.02 (3H, d, J=7 Hz), 1.23 (3H,t, J=7 Hz), 1.30-1.48 (2H, m), 1.60-1.72 (2H, m), 1.72-1.88 (1H, m),1.95-2.07 (1H, m), 2.27 (2H, t, J=7 Hz), 2.43 (3H, s), 3.44-3.54 (1H,m), 3.95 (1H, d, J=18 Hz), 4.03 (1H, d, J=18 Hz), 4.08 (2H, q, J=7 Hz),4.73 (1H, t, J=7 Hz), 8.06 (1H, s), 8.63 (1H, s), 9.02 (1H, s).

MS (ESI⁺): m/z 364.

Preparation 215

ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-8-isopropoxy-7-oxooctanoate

¹H NMR (CDCl₃) δ 0.88 (3H, d, J=7 Hz), 1.03 (3H, t, J=7 Hz), 1.23 (3H,t, J=7 Hz), 1.20-1.46 (2H, m), 1.58-1.72 (2H, m), 1.73-1.87 (1H, m),1.95-2.07 (1H, m), 2.27 (2H, 1, J=7 Hz), 3.46-3.58 (1H, m), 3.94 (1H, d,J=17 Hz), 4.03 (1H, d, J=17 Hz), 4.10 (2H, q, J=7 Hz), 4.68 (1H, t, J=7Hz), 8.40 (1H, t, J=2 Hz), 8.86 (1H, d, J=2 Hz), 9.08 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 428 430.

Preparation 216

ethyl 8-(acetyloxy)-6-[(5-methyl-3-pyridinyl)carbonyl]-7-oxooctanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.37-1.47 (2H, m), 1.60-1.77 (2H,m), 2.01 (3H, s), 1.97-2.08 (2H, m), 2.29 (2H, t, J=7 Hz), 2.44 (3H, s),4.10 (2H, q, J=7 Hz), 4.52 (1H, t, J=7 Hz), 4.68 (1H, d, J=18 Hz), 4.76(1H, d, J=18 Hz), 8.04 (1H, s), 8.66 (1H, s), 8.98 (1H, s).

MS (ESI⁺): m/z 364.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 21.

EXAMPLE 285ethyl[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acetate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.40 (3H,s), 2.50 (3H, s), 3.02 (2H, q, J=7 Hz), 3.44 (2H, s), 4.14 (2H, q, J=7Hz), 5.98 (1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz), 7.55 (1H, s), 8.45 (1H,s), 8.54 (1H, s).

MS (ESI⁺): m/z 338.

EXAMPLE 286 ethyl7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylate

¹H NMR (CDCl₃) δ 0.96 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.41 (3H,s), 2.61 (3H, s), 3.04 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 6.30 (1H,d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.58 (1H, s), 8.48 (1H, d, J=2 Hz),8.51 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 324.

EXAMPLE 287 ethyl4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 10.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.67-1.78(2H, m), 2.22 (2H, t, J=7 Hz), 2.42-2.54 (2H, m), 2.59 (3H, s), 3.01(2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.53 (1H,d, J=4 Hz), 7.87 (1H, m), 8.54 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 430 432.

EXAMPLE 288 ethyl3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.42 (2H,t, J=7 Hz), 2.85-2.97 (2H, m), 3.06 (2H, q, J=7 Hz), 3.46 (3H, s), 4.08(2H, q, J=7 Hz), 4.65 (2H, s), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4Hz), 7.87 (1H, m), 8.54 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 446 448.

EXAMPLE 289 ethyl4-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.60-1.75(2H, m), 2.17 (3H, s), 2.10-2.28 (2H, m), 2.45-2.60 (2H, m), 3.02 (2H,q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.32 (2H, s), 5.95 (1H, d, J=4 Hz),6.63 (1H, d, J=4 Hz), 7.88 (1H, m), 8.55 (1H, m), 8.78 (1H, m).

MS (ESI⁺): m/z 488 490.

EXAMPLE 290 benzyl5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.33-1.60(4H, m), 2.18 (2H, t, J=7 Hz), 2.35-2.47 (2H, m), 2.56 (3H, s), 3.03(2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 5.42 (2H, s), 5.82 (1H, d, J=4Hz), 6.53 (1H, d, J=4 Hz), 7.36-7.47 (5H, m), 8.33 (1H, m), 8.77 (1H, d,J=2 Hz), 933 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 500.

EXAMPLE 291 ethyl5-[2-[(benzyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.20-1.50(4H, m), 2.06 (2H, t, J=7 Hz), 2.42 (3H, s), 2.47-2.63 (2H, m), 3.05(2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.64 (2H, s), 4.73 (2H, s), 5.90(1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.27-7.39 (5H, m), 7.51 (1H, s),8.41 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz).

EXAMPLE 292 ethyl3-[2-[(benzyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.16 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.36 (2H,t, J=7 Hz), 2.42 (3H, s), 2.80-3.00 (2H, m), 3.06 (2H, q, J=7 Hz), 4.03(2H, q, J=7 Hz), 4.65 (2H, s), 4.75 (2H, s), 5.92 (1H, d, J=2 Hz), 6.59(1H, d, J=2 Hz), 7.26-7.38 (5H, m), 7.48 (1H, s), 8.40 (1H, d, J=2 Hz),8.53 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 458.

EXAMPLE 293 ethyl5-[2-[(cyclohexyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.20-1.60 (10H, m), 1.25 (3H, t, J=7 Hz), 1.37 (3H, t,J=7 Hz), 1.70-1.83 (2H, m), 1.96-2.07 (2H, m), 2.15 (2H, t, J=7 Hz),2.43 (3H, s), 2.53-2.68 (2H, m), 3.04 (2H, q, J=7 Hz), 3.42-3.53 (1H,m), 4.08 (2H, q, J=7 Hz), 4.69 (2H, s), 5.88 (1H, d, J=4 Hz), 6.55 (1H,d, J=4 Hz), 7.53 (1H, s), 8.42 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz).

EXAMPLE 294 ethyl5-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.22-1.62 (10H, m), 1.23 (3H, t, J=7 Hz), 1.37 (3H, t,J=7 Hz), 1.73-1.86 (2H, m), 1.98-2.07 (2H, m), 2.18 (2H, t, J=7 Hz),2.53-2.70 (2H, m), 3.03 (2H, q, J=7 Hz), 3.42-3.56 (1H, m), 4.12 (2H, q,J=7 Hz), 4.69 (2H, s), 5.88 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.88(1H, m), 8.54 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz).

EXAMPLE 295 ethyl3-[2-[(cyclohexyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.19 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.16-1.45(4H, m), 1.52-1.65 (2H, m), 1.73-1.83 (2H, m), 1.98-2.07 (2H, m),2.35-2.47 (2H, m), 2.42 (3H, s), 2.84-2.98 (2H, m), 3.03 (2H, q, J=7Hz), 3.45-3.56 (1H, m), 4.06 (2H, q, J=7 Hz), 4.71 (2H, s), 5.89 (1H, d,J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.50 (1H, s), 8.42 (1H, s), 8.53 (1H, s).

MS (ESI⁺): m/z 450.

EXAMPLE 296 ethyl3-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}propanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.15-1.60(6H, m), 1.73-1.85 (2H, m), 1.97-2.08 (2H, m), 2.45 (2H, t, J=7 Hz),2.83-2.97 (2H, m), 3.05 (2H, q, J=7 Hz), 3.42-3.56 (1H, m), 4.08 (2H, q,J=7 Hz), 4.71 (2H, s), 5.90 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.86(1H, t, J=2 Hz), 8.53 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 514 516.

EXAMPLE 297 ethyl5-[7-ethyl-2-(isopropoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.26 (6H, d, J=7 Hz), 1.37 (3H,t, J=7 Hz), 1.38-1.62 (4H, m), 2.17 (2H, t, J=7 Hz), 2.43 (3H, s),2.53-2.68 (2H, m), 3.03 (2H, q, J=7 Hz), 3.76-3.88 (1H, m), 4.08 (2H, q,J=7 Hz), 4.66 (2H, s), 5.88 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.52(1H, s), 8.42 (1H, s), 8.53 (1H, s).

MS (ESI⁺): m/z 438.

EXAMPLE 298 ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isopropoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.25 (6H, d, J=7 Hz), 1.37 (3H,t, J=7 Hz), 1.37-1.64 (4H, m), 2.15 (2H, t, J=7 Hz), 2.54-2.72 (2H, m),3.02 (2H, q, J=7 Hz), 3.75-3.87 (1H, m), 4.09 (2H, q, J=7 Hz), 4.66 (2H,s), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.88 (1H, m), 8.55 (1H,d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 502 504.

EXAMPLE 299 ethyl5-[2-[(acetyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.30-158(4H, m), 2.13 (2H, t, J=7 Hz), 2.18 (3H, s), 2.44 (3H, s), 2.40-2.55(2H, m), 3.02 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 5.29 (2H, s), 5.93(1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.52 (1H, s), 8.42 (1H, s), 8.53(1H, s).

MS (ESI⁺): m/z 438.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 236.

EXAMPLE 300 ethyl4-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.41 (3H,t, J=7 Hz), 1.68-1.80 (2H, m), 2.22 (2H, t, J=7 Hz), 2.44-2.54 (2H, m),2.59 (3H, s), 3.03 (2H, q, J=7 Hz), 3.95 (2H, q, J=7 Hz), 4.10 (2H, q,J=7 Hz), 4.36 (1H, d, J=3 Hz), 4.77 (1H, d, J=3 Hz), 5.88 (1H, d, J=4Hz), 6.52 (1H, d, J=4 Hz), 7.92 (1H, m), 8.53 (1H, d, J=2 Hz), 8.93 (1H,d, J=2 Hz).

MS (ESI⁺): m/z 422.

EXAMPLE 301 ethyl3-[4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.19 (3H, 1, J=7 Hz), 1.26 (3H, t, J=7 Hz), 1.37 (3H,t, J=7 Hz), 2.42 (2H, t, J=7 Hz), 2.84-2.97 (2H, m), 3.07 (2H, q, J=7Hz), 3.47 (3H, s), 3.97 (2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.36 (1H,d, J=3 Hz), 4.66 (2H, s), 4.77 (1H, d, J=3 Hz), 5.95 (1H, d, J=4 Hz),6.61 (1H, d, J=4 Hz), 7.92 (1H, m), 8.54 (1H, d, J=2 Hz), 8.95 (1H, d,J=2 Hz).

MS (ESI⁺): m/z 438.

EXAMPLE 302 ethyl3-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.18 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.40 (2H,t, J=7 Hz), 2.84-2.98 (2H, m), 3.03 (2H, q, J=7 Hz), 3.47 (3H, s), 4.04(2H, q, J=7 Hz), 4.65 (2H, s), 5.46 (1H, d, J=11 Hz), 5.87 (1H, d, J=18Hz), 5.94 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 6.72-6.83 (1H, dd, J=11Hz, 18 Hz), 7.74 (1H, m), 8.49 (1H, d, J=2 Hz), 8.72 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 394.

EXAMPLE 303 methyl4-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.65-1.78 (2H, m), 2.23 (2H, t,J=7 Hz), 2.54-2.70 (2H, m), 3.05 (2H, q, J=7 Hz), 3.47 (3H, s), 3.58(3H, s), 4.67 (2H, s), 5.46 (1H, d, J=11 Hz), 5.88 (1H, d, J=18 Hz),5.93 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 6.73-6.83 (1H, dd, J=11 Hz,18 Hz), 7.77 (1H, m), 8.51 (1H, d, J=2 Hz), 8.71 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 394.

EXAMPLE 304 methyl4-[4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.67-1.82(2H, m), 2.22 (2H, t, J=7 Hz), 2.53-2.67 (2H, m), 3.04 (2H, q, J=7 Hz),3.47 (3H, s), 3.58 (3H, s), 3.95 (2H, q, J=7 Hz), 4.34 (1H, d, J=2 Hz),4.67 (2H, s), 4.77 (1H, d, J=2 Hz), 5.93 (1H, d, J=4 Hz), 6.59 (1H, d,J=4 Hz), 7.92 (1H, m), 8.54 (1H, d, J=2 Hz), 8.95 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 438.

EXAMPLE 305 ethyl3-{4-[5-(1-ethoxyvinyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}propanoate

¹H NMR (CDCl₃) δ 1.19 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.44 (3H,t, J=7 Hz), 2.33-2.43 (2H, m), 2.58 (3H, s), 2.76-2.87 (2H, m), 3.03(2H, q, J=7 Hz), 3.96 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 4.36 (1H,d; J=2 Hz), 4.77 (1H, d, J=2 Hz), 5.91 (1H, d, J=4 Hz), 6.54 (1H, d, J=4Hz), 7.91 (1H, m), 8.53 (1H, d, J=2 Hz), 8.96 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 408.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 251.

EXAMPLE 306 ethyl4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.19 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.66-1.82(2H, m), 2.21 (2H, t, J=7 Hz), 2.41-2.51 (2H, m), 2.60 (3H, s), 2.69(3H, s), 3.03 (2H, q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 5.83 (1H, d, J=4Hz), 6.53 (1H, d, J=4 Hz), 8.25 (1H, m), 8.79 (1H, d, J=2 Hz), 9.25 (1H,d, J=2 Hz).

MS (ESI⁺): m/z 394.

EXAMPLE 307 ethyl3-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.18 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.41 (2H,t, J=7 Hz), 2.70 (3H, s), 2.83-2.96 (2H, m), 3.06 (2H, q, J=7 Hz), 3.47(3H, s), 4.03 (2H, q, J=7 Hz), 4.66 (2H, s), 5.88 (1H, d, J=4 Hz), 6.61(1H, d, J=4 Hz), 8.26 (1H, m), 8.79 (1H, d, J=2 Hz), 9.25 (1H, d, J=2Hz).

EXAMPLE 308 methyl4-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.64-1.80 (2H, m), 2.20 (2H, t,J=7 Hz), 2.53-2.65 (2H, m), 2.70 (3H, s), 3.05 (2H, q, J=7 Hz), 3.47(3H, s), 3.57 (3H, s), 4.67 (2H, s), 5.87 (1H, d, J=4 Hz), 6.60 (1H, d,J=4 Hz), 8.27 (1H, s), 8.81 (1H, d, J=2 Hz), 9.26 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 410.

EXAMPLE 309 ethyl3-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.19 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.33-2.42(2H, m), 2.59 (3H, s), 2.69 (3H, s), 2.75-2.83 (2H, m), 3.02 (2H, q, J=7Hz), 4.05 (2H, q, J=7 Hz), 5.83 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz),8.25 (1H, m), 8.78 (1H, d, J=2 Hz), 9.26(1H, d, J=2 Hz).

MS (ESI⁺): m/z 380.

EXAMPLE 310

A mixture of benzyl5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinate(330 mg) and 10% palladium on carbon (33 mg) in methanol (10 mL) wasstirred under 4 atm hydrogen atmosphere at ambient temperature for 2hours. The catalysts were filterred off and washed with chloroform. Thefiltrates were evaporated in vacuo to give5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinicacid as yellow oil (272 mg).

5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinicacid

¹H NMR (CDCl₃) δ 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.35-1.63(4H, m), 2.19 (2H, t, J=7 Hz), 2.38-2.49 (2H, m), 2.57 (3H, s), 3.03(2H, q, J=7 Hz), 4.11 (2H, q, J=7 Hz), 5.85 (1H, d, J=4 Hz), 6.53 (1H,d, J=4 Hz), 8.40 (1H, m), 8.83 (1H, d, J=2 Hz), 937 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 408, MS (ESI⁺): m/z 410.

EXAMPLE 311

To a solution of5-[3-(5-ethoxy-5-oxopentyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]nicotinicacid (235 mg) and triethylamine (87.1 mg) in t-butanol (10 mL) was addeddiphenylphosphoryl azide (237 mg) and the mixture was heated underreflux for 2 hours. After evaporation of solvent, the residue waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was purified by silica gel columnchromatography eluting with a mixture of hexane and ethyl acetate(20:1-2:1) to give ethyl5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl)pentanoateas yellow oil (190 mg).

ethyl5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl)pentanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.42-1.67(4H, m), 1.52 (9H, s), 2.19-2.28 (2H, m), 2.38-2.50 (2H, m), 2.55 (3H,s), 3.03 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.92 (1H, d, J=4 Hz),6.53 (1H, d, J=4 Hz), 6.93 (1H, br), 7.87 (1H, s), 8.30 (1H, d, J=2 Hz),8.70 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 481.

EXAMPLE 312

A solution of ethyl5-(4-{5-[(tert-butoxycarbonyl)amino]-3-pyridinyl}-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl)pentanoate(190 mg) in 2 N hydrogen chloride ethyl acetate solution (4 mL) wasstirred at ambient temperature for 2 hours. After evaporation ofsolvent, the residue was partitioned between ethyl acetate and saturatedsodium bicarbonate solution. The organic layer was separated, washedwith brine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by silica gel column chromatography eluting with amixture of chloroform and methanol (100:1-20:1) to give ethyl5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoateas yellow oil (140 mg).

ethyl5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.65(4H, m), 2.23 (2H, t, J=7 Hz), 2.45 (2H, t, J=7 Hz), 2.54 (3H, s), 3.03(2H, q, J=7 Hz), 3.97 (2H, br), 4.12 (2H, q, J=7 Hz), 5.94 (1H, d, J=4Hz), 6.53 (1H, d, J=4 Hz), 7.02 (1H, m), 8.02 (1H, d, J=2 Hz), 8.17 (1H,d, J=2 Hz).

MS (ESI⁺): m/z 381 (M+H).

EXAMPLE 313

To a solution of ethyl5-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate(55 mg), 37% formaldehyde solution (277 mg) and sodium cyanoborohydride(273 mg) in acetnitrile (1 mL) and methanol (1 mL) was added acetic acid(2 drops) and the mixture was stirred at ambient temperature for 2hours. The solution was diluted with saturated sodium bicarbonatesolution and extracted with chloroform. The organic layer was washedwith brine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by preparative silica gel column chromatographyeluting with a mixture of chloroform and methanol (20:1) to give ethyl5-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoateas yellow oil (365 mg).

ethyl5-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.63(4H, m), 2.19 (2H, t, J=7 Hz), 2.40-2.53 (2H, m), 2.55 (3H, s), 3.02(6H, s), 3.03 (2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 5.93 (1H, d, J=4Hz), 6.50 (1H, d, J=4 Hz), 6.96 (1H, m), 7.95 (1H, d, J=2 Hz), 8.20 (1H,d, J=2 Hz).

MS (ESI⁺): m/z 409.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 245.

EXAMPLE 3143-[7-ethyl-4-(5-ethyl-3-pyridinyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 1.29 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.45-2.58(2H, m), 2.73 (2H, q, J=7 Hz), 2.82-3.02 (2H, m), 3.03 (2H, q, J=7 Hz),3.47 (3H, s), 4.67 (2H, s), 5.91 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz),7.58 (1H, m), 8.43 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 366, MS (ESI⁺): m/z 368.

EXAMPLE 3154-[7-ethyl-4-(5-ethyl-3-pyridinyl)-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (CDCl₃) δ 1.31 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.69-1.85(2H, m), 2.20-2.31 (2H, m), 2.52-2.75 (2H, m), 2.77 (2H, q, J=7 Hz),3.06 (2H, q, J=7 Hz), 3.46 (3H, s), 4.60-4.80 (2H, m), 5.91 (1H, d, J=4Hz), 6.58 (1H, d, J=4 Hz), 7.61 (1H, s), 8.44-8.53 (2H, m).

MS (ESI⁺): m/z 382.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 228.

EXAMPLE 316 methyl4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.65-1.79 (2H, m), 2.25 (2H, t,J=7 Hz), 2.39-2.53 (2H, m), 3.06 (2H, q, J=7 Hz), 3.61 (3H, s), 4.90(2H, s), 5.96 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.88 (1H, m), 8.55(1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 432 434.

EXAMPLE 317 ethyl5-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.35-1.60(4H, m), 2.17 (2H, t, J=7 Hz), 2.35-2.45 (2H, m), 2.43 (3H, s), 3.04(2H, q, J=7 Hz), 3.83 (1H, t, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.85 (2H,d, J=7 Hz), 5.96 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.50 (1H, s),8.42 (1H, s), 8.54 (1H, s).

MS (ESI⁺): m/z 396.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 268.

EXAMPLE 318 methyl4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.65-1.79 (2H, m), 2.24 (2H, t,J=7 Hz), 2.52-2.70 (2H, m), 3.04 (2H, q, J=7 Hz), 3.46 (3H, s), 3.60(3H, s), 4.76 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.88(1H, m), 8.56 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 446 448.

EXAMPLE 319 ethyl5-[2-[(2-tert-butoxy-2-oxoethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.30-1.60(4H, m), 1.47 (9H, s), 2.17 (2H, t, J=7 Hz), 2.43 (3H, s), 2.58-2.72(2H, m), 3.03 (2H, q, J=7 Hz), 4.08 (2H, s), 4.12 (2H, q, J=7 Hz), 4.81(2H, s), 5.91 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.53 (1H, s), 8.43(1H, s), 8.53 (1H, s).

MS (ESI⁺): m/z 510.

EXAMPLE 320 ethyl5-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 0.20-0.32 (2H, m), 0.53-0.63 (2H, m), 1.07-1.20 (1H,m), 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60 (4H, m), 2.15(2H, t, J=7 Hz), 2.43 (3H, s), 2.53-2.68 (2H, m), 3.02 (2H, q, J=7 Hz),3.41 (2H, d, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.70 (2H, s), 5.89 (1H, d,J=4 Hz), 6.56 (1H, d, J=4 Hz), 7.52 (1H, s), 8.43 (1H, s), 8.53 (1H, s).

MS (ESI⁺): m/z 450.

EXAMPLE 321 ethyl5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 0.88-1.05 (2H, m), 1.16-1.35 (4H, m), 1.25 (3H, t, J=7Hz), 1.37 (3H, t, J=7 Hz), 1.38-1.59 (4H, m), 1.60-1.87 (5H, m), 2.16(2H, t, J=7 Hz), 2.43 (3H, s), 2.54-2.67 (2H, m), 3.03 (2H, q, J=7 Hz),3.35 (2H, d, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.64 (2H, s), 5.89 (1H, d,J=4 Hz), 6.56 (1H, d, J=4 Hz), 7.52 (1H, s), 8.43 (1H, d, J=2 Hz), 8.53(1H, d, J=2 Hz).

MS (ESI⁺): m/z 492.

EXAMPLE 322 ethyl5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.35-1.54(4H, m), 2.12 (2H, t, J=7 Hz), 2.43 (3H, s), 2.50-2.63 (2H, m), 3.03(2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.66 (2H, s), 4.76 (2H, s), 5.92(1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.28 (1H, m), 7.52 (1H, s), 7.72(1H, d, J=8 Hz), 8.42 (1H, d, J=2 Hz), 8.54 (2H, m), 8.62 (1H, d, J=2Hz).

MS (ESI⁺): m/z 487.

EXAMPLE 323 ethyl5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.21 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.36-1.54(4H, m), 2.12 (2H, t, J=7 Hz), 2.42 (3H, s), 2.56-2.68 (2H, m), 3.03(2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.77 (2H, s), 4.85 (2H, s), 5.92(1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.22 (1H, m), 7.43-7.54 (2H, m),7.66-7.74 (1H, m), 8.42 (1H, d, J=2 Hz), 8.54 (1H, d, J=2 Hz), 8.57 (1H,d, J=5 Hz).

MS (ESI⁺): m/z 487.

EXAMPLE 324 ethyl5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.38-1.57(4H, m), 2.12 (2H, t, J=7 Hz), 2.43 (3H, s), 2.52-2.68 (2H, m), 3.05(2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.66 (2H, s), 4.77 (2H, s), 5.93(1H, d, J=4 Hz), 6.60 (1H, d, J=2 Hz), 7.28 (2H, d, J=7 Hz), 7.52 (1H,s), 8.42 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz), 858 (2H, d, J=7 Hz).

MS (ESI⁺): m/z 487.

EXAMPLE 325 ethyl5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.38-1.57(4H, m), 2.13 (2H, t, J=7 Hz), 2.43 (3H, s), 2.52-2.68 (2H, m), 3.03(2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 4.82 (2H, s), 4.88 (2H, m), 5.92(1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.52 (1H, s), 8.43 (1H, d, J=2Hz), 8.48-8.57 (3H, m), 8.75 (1H, m).

MS (ESI⁺): m/z 488.

EXAMPLE 326 ethyl5-[4-(3-cyanophenyl)-2-(ethoxymethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.18-1.29 (6H, m), 1.34-1.53 (7H, m), 2.14 (2H, t, J=7Hz), 2.52 (2H, m), 3.02 (2H, q, J=7 Hz), 3.53 (2H, q, J=7 Hz), 4.07 (2H,q, J=7 Hz), 4.66 (1H, s), 5.73 (1 J, d, J=5 Hz), 6.56 (1H, d, J=5 Hz),7.60 (2H, m), 7.67 (1H, s), 7.75 (1H, m)

EXAMPLE 327 ethyl5-[2-[(benzyloxy)methyl]-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.30-1.46 (7H, m), 2.06 (2H, t,J=7 Hz), 2.51 (2H, m), 3.02 (2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 4.64(3H, s), 4.72 (3H, s), 5.83 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz),7.25-7.38 (5H, m), 7.57 (2H, d, J=9 Hz), 7.65 (1H, s), 7.74 (1H, m).

EXAMPLE 328 methyl4-({[4-(3-cyanophenyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methoxy}methyl)benzoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.32-1.49 (7H, m), 2.01 (2H, t,J=7 Hz), 2.52 (2H, m), 3.02 (2H, t, J=7 Hz), 3.92 (3H, s), 4.07 (2H, t,J=7 Hz), 4.69 (2H, s), 4.75 (2H, s), 6.84 (1H, d, J=5 Hz), 6.59 (1H, d,J=5 Hz), 7.43 (2H, d, J=9 Hz), 7.60 (2H, m), 7.65 (1H, s), 7.75 (1H, m),8.02 (2H, d, J=9 Hz).

EXAMPLE 329

A solution of ethyl5-[2-[(2-tert-butoxy-2-oxoethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(60 mg) in tifluoroacetic acid (2 mL) was stirred at ambient temperaturefor 2 hours, and evaporated in vacuo to give{[3-(5-ethoxy-5-oxopentyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl]methoxy}aceticacid as brown oil (55 mg).

{[3-(5-ethoxy-5-oxopentyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl]methoxy}aceticacid

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.35-1.60(4H, m), 2.23 (2H, t, J=7 Hz), 2.50-2.58 (2H, m), 2.67 (3H, s), 3.03(2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.30 (2H, s), 4.87 (2H, s), 5.86(1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 8.15 (1H, s), 8.69 (1H, s), 8.85(1H, s).

MS (ESI⁻): m/z 452, MS (ESI⁺): m/z 454.

EXAMPLE 330

To a solution of{[3-(5-ethoxy-5-oxopentyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-2-yl]methoxy}aceticacid (55 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimidehydrochloride (34.9 mg) and 1-hydroxybenotriazole (24.6 mg) indimethylformamide (2 mL) was added morpholine (12.7 mg) and the mixturewas stirred at ambient temperature for 1 hour. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with saturated sodium bicarbonate solution, water andbrine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by silica gel column chromatography eluting with amixture of ethyl acetate and methanol (50:1-20:1) to give ethyl5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2-oxoethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoateas yellow oil (50 mg).

ethyl5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2-oxoethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.63(4H, m), 2.15 (2H, t, J=7 Hz), 2.43 (3H, s), 2.54-2.68 (2H, m), 3.02(2H, q, J=7 Hz), 3.48-357 (2H, m), 3.63-3.78 (6H, m), 4.08 (2H, q, J=7Hz), 4.30 (2H, s), 4.78 (2H, s), 5.93 (H, d, J=4 Hz), 6.60 (1H, d, J=4Hz), 7.52 (1H, s), 8.43 (1H, d, J=2 Hz), 8.54 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 523.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 330.

EXAMPLE 331 ethyl5-[7-ethyl-2-{[2-(methylamino)-2-oxoethoxy]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.38-1.62(4H, m), 2.18 (2H, t, J=7 Hz), 2.44 (3H, s), 2.48-2.62 (2H, m), 2.88(3H, d, J=7 Hz), 3.03 (2H, q, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.13 (2H,s), 4.77 (2H, s), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 6.79 (1H,br), 753 (1H, s), 8.44 (1H, s), 8.56 (1H, s).

MS (ESI⁺): m/z 467.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 271.

EXAMPLE 332 ethyl5-[2-[(benzylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.30-1.50(2H, m), 1.60-1.85 (2H, m), 2.12 (2H, t, J=7 Hz), 2.30-2.45 (2H, m),2.42 (3H, s), 3.03 (2H, q, J=7 Hz), 3.96 (2H, s), 3.98 (2H, s), 4.08(2H, q, J=7 Hz), 5.87 (1H, d, J=4 Hz), 6.54 (1H, d, J=4 Hz), 7.27-7.43(5H, m), 7.48 (1H, s), 8.38 (1H, d, J=2 Hz), 853 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 485.

EXAMPLE 333

A mixture of ethyl5-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(100 mg), 1H-isoindole-1,3(2H) dione (44.6 mg) diisopropylazodicarboxylate (76.7 mg) and triphenylphosphine (99.5 mg) intetrahydrofuran (2 mL) was stirred at ambient temperature for 1 hour.After evaporation of solvent, the residue was purified by silica gelcolumn chromatography eluting with a mixture of hexane and ethyl acetate(20:1-1:1) to give ethyl5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoateas yellow oil (107 mg).

ethyl5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 0.89 (3H, t, J=7 Hz), 1.26 (3H, t, J=7 Hz), 1.20-1.40(2H, m), 1.53-1.75 (2H, m), 2.24 (2H, t, J=7 Hz), 2.44 (3H, s), 2.47(2H, q, J=7 Hz), 2.50-2.64 (2H, m), 4.12 (2H, q, J=7 Hz), 5.10 (2H, s),5.85 (1H, d, J=4 Hz), 6.43 (1H, d, J=4 Hz), 7.51 (1H, s), 7.78 (2H, m),7.96 (2H, m), 8.43 (1H, s), 8.55 (1H, s).

MS (ESI⁺): m/z 525.

EXAMPLE 334

A mixture of ethyl5-[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(107 mg) and hydrazine monohydrate (51.1 mg) in ethanol (2 mL) washeated under reflux for 2 hours. After evaporation of solvent, theresidue was partitioned between chloroform and saturated sodiumbicarbonate solution. The organic layer was separated, washed withbrine, dried over magnesium sulfate, and evaporated in vacuo to giveethyl5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoateas yellow oil (67.6 mg).

ethyl5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.38-1.62(4H, m), 2.14 (2H, t, J=7 Hz), 2.42 (3H, s), 2.38-2.56 (2H, m), 3.04(2H, q, J=7 Hz), 4.06 (2H, s), 4.08 (2H, q, J=7 Hz), 5.90 (1H, d, J=4Hz), 6.55 (1H, d, J=4 Hz), 7.51 (1H, s), 8.41 (1H, s), 8.53 (1H, s).

MS (ESI⁺): m/z 395.

EXAMPLE 335

A mixture of ethyl5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(67.6 mg) and acetic anhydride (19.2 mg) in dichloromethane (3 mL) wasstirred at ambient temperature for 1 hour. The solution was diluted withchloroform, washed with saturated sodium bicarbonate solution and brine,dried over magnesium sulfate, and evaporated in vacuo. The residue waspurified by preparative silica gel column chromatography eluting with amixture of chloroform and methanol (20:1) to give ethyl5-[2-[(acetylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoateas yellow oil (70 mg).

ethyl5-[2-[(acetylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.40 (3H, t, J=7 Hz), 1.40-1.63(4H, m), 2.12 (2H, m), 2.15 (3H, s), 2.43 (3H, s), 2.40-2.53 (2H, m),3.03 (2H, q, J=7 Hz), 4.10 (2H, q, J=7 Hz), 4.66 (2H, m), 5.94 (1H, d,J=4 Hz), 6.59 (1H, d, J=4 Hz), 6.85 (1H, br), 750 (1H, s), 8.40 (1H, d,J=2 Hz), 8.54 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 437.

EXAMPLE 336

To a solution of ethyl5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(80 mg) and pyridine (1 mL) in dichloromethane (2 mL) was addedmethanesulfonyl chloride (34.8 mg) under ice-water cooling and themixture was stirred at ambient temperature for 1 hour. The solution wasdiluted with chloroform, washed with saturated sodium bicarbonatesolution and brine, dried over magnesium sulfate, and evaporated invacuo. The residue was purified by preparative silica gel columnchromatography eluting with a mixture of chloroform and methanol (20:1)to give ethyl5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(methylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoateas yellow oil (62.8 mg)

ethyl5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(methylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.40-1.62(4H, m), 2.19 (2H, t, J=7 Hz), 2.44 (3H, s), 2.38-2.51 (2H, m), 3.02(2H, q, J=7 Hz), 3.06 (3H, s), 4.08 (2H, q, J=7 Hz), 4.58 (2H, s), 5.63(1H, br), 5.97 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.50 (1H, s), 8.41(1H, d, J=2 Hz), 8.54 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 473.

EXAMPLE 337

A mixture of ethyl5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(75 mg), benzoic acid (27.9 mg),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (54.7 mg)and 1-hydroxybenotriazole (385 mg) in dimethylformamide (2 mL) wasstirred at ambient temperature for 2 hours. The mixture was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith saturated sodium bicarbonate solution, water and brine, dried overmagnesium sulfate, and evaporated in vacuo. The residue was purified bypreparative silica gel column chromatography eluting with a mixture ofchloroform and methanol (20:1) to give ethyl5-[2-[(benzoylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoateas yellow oil (60 mg).

ethyl5-[2-[(benzoylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.42 (3H, t, J=7 Hz), 1.42-1.65(4H, m), 2.17 (2H, t, J=7 Hz), 2.44 (3H, s), 2.44-2.58 (2H, m), 3.06(2H, q, J=7 Hz), 4.08 (2H, q, J=7 Hz), 4.86 (2H, m), 5.96 (1H, d, J=4Hz), 6.60 (1H, d, J=4 Hz), 7.46-7.59 (4H, m), 7.78 (1H, br), 7.91-7.97(2H, m), 8.44 (1H, d, J=2 Hz), 8.56 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 499.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 337.

EXAMPLE 338 ethyl5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(2-pyrazinylcarbonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.41 (3H, t, J=7 Hz), 1.42-1.64(4H, m), 2.18 (2H, t, J=7 Hz), 2.44 (3H, s), 2.47-2.59 (2H, m), 3.08(2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 4.89 (2H, d, J=7 Hz), 5.96 (1H,d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.53 (1H, s), 8.43 (1H, d, J=2 Hz),8.55 (1H, d, J=2 Hz), 8.62 (1H, m), 8.79 (1H, m), 9.15 (1H, br), 9.46(1H, m).

MS (ESI⁺): m/z 501.

EXAMPLE 339

To a solution of ethyl5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(80 mg) and pyridine (1 mL) in dichloromethane (2 mL) was added methylchloridocarbonate (34.8 mg) under ice-water cooling and the mixture wasstirred at ambient temperature for 2 hours.

After evaporation of solvent, the residue was partitioned between ethylacetate and water. The organic layer was separated, washed withsaturated sodium bicarbonate solution and brine, dried over magnesiumsulfate, and evaporated in vacuo. The residue was purified bypreparative silica gel column chromatography eluting with a mixture ofchloroform and methanol (20:1) to give ethyl5-[7-ethyl-2-{[(methoxycarbonyl)amino]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoateas yellow oil (70 mg).

ethyl5-[7-ethyl-2-{[(methoxycarbonyl)amino]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.40-1.63(4H, m), 2.19 (2H, t, J=7 Hz), 2.44 (3H, s), 2.40-2.55 (2H, m), 3.03(2H, q, J=7 Hz), 3.07 (3H, s), 4.12 (2H, q, J=7 Hz), 4.57 (2H, m), 5.72(1H, br), 5.97 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.51 (1H, s), 8.41(1H, s), 8.56 (1H, s).

EXAMPLE 340

To a solution of ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(70.0 mg) and triethyl amine (185 mg) in dichloromethane (1 mL) wasadded methanesulfonyl chloride (20.9 mg) under an ice bath. Afterstirring for 1 hour, to the mixture was added 1-methylpiperazine (27.0mg). The mixture was stirred for 0.5 hour under an ice bath andovernight at room temperature. The mixture was partitioned between ethylacetate and water. The organic layer was washed with brine, dried overmagnesium sulfate, and evaporated. Preparative silica gel thin layerchromatography (chloroform-methanol=20-1) afforded ethyl5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoateas an yellow gum (52.4 mg, 63.5%).

ethyl5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃): 1.23 (3H, t, J=7 Hz), 1.33-1.60 (7H, m), 2.16 (2H, t,J=7 Hz), 2.29 (3H, s), 2.34-2.65 (6H, m), 3.00 (2H, q, J=7 Hz), 3.54(2H, s), 4.08 (2H, q, J=7 Hz), 5.86 (1H, d, J=5 Hz), 6.55 (1H, d, J=5 Hz9, 7.87 (1H, m), 8.54 (1H, m), 8.77 (1H, m).

EXAMPLE 341

To a solution of ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate(300 mg, 0.652 mmol) and tetrabromomethane (432 mg, 1.30 mmol) intetrahydrofuran (3 mL) was added triphenylphosphine (308 mg, 1.17 mmol)over 40 minutes. The mixture was concentrated, and the residue waschromatographed on a flash silica gel column chromatography (ethylacetate-hexane=1-8 to 1-5) to afford ethyl5-[2-(bromomethyl)-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoateas an yellow gum (229 mg, 50.4%).

ethyl5-[2-(bromomethyl)-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.41-1.50(4H, m), 2.19 (2H, t, J=7 Hz), 2.58 (2H, m), 3.01 (2H, q, J=7 Hz), 4.08(2H, q, J=7 Hz), 4.66 (2H, s), 5.94 (1H, d, J=5 Hz), 6.63 (1H, d, J=5Hz), 7.88 (1H, m), 8.55 (1H, m), 8.79 (1H, m).

EXAMPLE 342

A mixture of ethyl5-[2-(bromomethyl)-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate(70.0 mg) and potassium cyanide (13.1 mg) in N,N-dimethylformamide (1mL) was stirred for 28 hours at room temperature. The mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with water (two times), brine, dried over magnesium sulfate, andevaporated to give ethyl5-[4-(5-bromo-3-pyridinyl)-2-(cyanomethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoateas an yellow gum (28.8 mg, 45.9%).

ethyl5-[4-(5-bromo-3-pyridinyl)-2-(cyanomethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.46-1.65 (7H, m), 2.22 (2H, t,J=7 Hz), δ 2.48 (2H, m), 3.04 (2H, q, J=7 Hz), 3.98 (2H, s), 4.10 (2H,q, J=7 Hz), 5.98 (1H, d, J=5 Hz), 6.65 (1H, d, J=5 Hz), 7.88 (1H, m),8.55 (1H, m), 8.81 (1H, m).

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 76.

EXAMPLE 343[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]aceticacid

¹H NMR (CDCl₃) δ 1.36 (3H, t, J=7 Hz), 2.45 (3H, s), 2.56 (3H, s), 3.02(2H, q, J=7 Hz), 3.28 (1H, d, J=17 Hz), 3.53 (1H, d, J=17 Hz), 5.91 (1H,d, J=4 Hz), 6.52 (1H, d, J=4 Hz), 7.71 (1H, s), 8.47 (1H, s), 8.59 (1H,s).

MS (ESI⁻): m/z 308, MS (ESI⁺): m/z 310.

EXAMPLE 3444-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.65-1.85 (2H, m), 2.31 (2H, t,J=7 Hz), 2.45-2.63 (2H, m), 2.59 (3H, s), 3.03 (2H, q, J=7 Hz), 5.88(1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.90 (1H, s), 8.53 (1H, s), 8.75(1H, s).

MS (ESI⁻): m/z 400 402, MS (ESI⁺): m/z 402 404.

EXAMPLE 3454-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.68-1.82 (2H, m), 2.26 (2H, t,J=7 Hz), 2.45-2.58 (2H, m), 2.60 (3H, s), 2.70 (3H, s), 3.03 (2H, q, J=7Hz), 5.83 (1H, d, J=4 Hz), 6.54 (1H, d, J=4 Hz), 8.28 (1H, m), 8.77 (1H,d, J=2 Hz), 9.19 (1H, d, J=2 Hz).

EXAMPLE 3463-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.49 (2H, t, J=7 Hz), 2.80-3.00(2H, m), 3.05 (2H, q, J=7 Hz), 3.46 (3H, s), 4.66 (2H, s), 5.94 (1H, d,J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.88 (1H, s), 8.55 (1H, s), 8.77 (1H, s).

MS (ESI⁻): m/z 416 418, MS (ESI⁺): m/z 418 420.

EXAMPLE 3473-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.48 (2H, t, J=7 Hz), 2.68 (3H,s), 2.85-2.97 (2H, m), 3.05 (2H, q, J=7 Hz), 3.47 (3H, s), 4.67 (2H, s),5.88 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 8.27 (1H, m), 8.78 (1H, d,J=2 Hz), 9.23 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 380, MS (ESI⁺): m/z 382.

EXAMPLE 3483-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.46-2.58 (2H, m), 2.83-3.03 (2H,m), 3.05 (2H, q, J=7 Hz), 3.47 (3H, s), 4.68 (2H, s), 5.46 (1H, d, J=11Hz), 5.88 (1H, d, J=18 Hz), 5.93 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz),6.68-6.82 (1H, dd, J=11 Hz, 18 Hz), 7.78 (1H, m), 8.47 (1H, d, J=2 Hz),8.68 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 364, MS (ESI⁺): m/z 366.

EXAMPLE 3494-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.68-1.82 (2H, m), 2.29 (2H, t,J=7 Hz), 2.55-2.75 (2H, m), 3.04 (2H, q, J=7 Hz), 3.45 (3H, s), 4.64(2H, s), 5.93 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.91 (1H, m), 8.56(1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 430 432, MS (ESI⁺): m/z 432 434.

EXAMPLE 3504-[7-ethyl-2-(methoxymethyl)-4-(5-vinyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.72-1.87 (2H, m), 2.26 (2H, t,J=7 Hz), 2.53-2.80 (2H, m), 3.06 (2H, q, J=7 Hz), 3.46 (3H, s), 4.68(2H, m), 5.47 (1H, d, J=11 Hz), 5.88 (1H, d, J=18 Hz), 5.93 (1H, d, J=4Hz), 6.59 (1H, d, J=4 Hz), 6.72-6.83 (1H, dd, J=11 Hz, 18 Hz), 7.81 (1H,m), 8.50 (1H, d, J=2 Hz), 8.63 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 378, MS (ESI⁺): m/z 380.

EXAMPLE 3514-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.66-1.83 (2H, m), 2.26 (2H, t,J=7 Hz), 2.55-2.70 (2H, m), 2.70 (3H, s), 3.05 (2H, q, J=7 Hz), 3.46(3H, s), 4.67 (2H, s), 5.88 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 8.29(1H, m), 8.80 (1H, d, J=2 Hz), 9.22 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 394, MS (ESI⁺): m/z 396.

EXAMPLE 3525-[4-(5-amino-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.34 (3H, t, J=7 Hz), 1.44-1.65 (4H, m), 2.16-2.32 (2H,m), 2.34-2.46 (2H, m), 2.53 (3H, s), 3.02 (2H, q, J=7 Hz), 5.06 (2H,br), 5.86 (1H, d, J=4 Hz), 5.98 (1H, d, J=4 Hz), 7.45 (1H, s), 7.84 (1H,s), 8.58 (1H, s).

MS (ESI⁻): m/z 351, MS (ESI⁺): m/z 353.

EXAMPLE 3535-{4-[5-(dimethylamino)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.40-1.70 (4H, m), 2.23 (2H, m),2.36-2.50 (2H, m), 2.56 (3H, s), 3.03 (2H, q, J=7 Hz), 3.06 (6H, s),5.88 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.13 (1H, s), 7.90 (1H, s),8.14 (1H, m).

MS (ESI⁺): m/z 381.

EXAMPLE 3543-[4-(5-acetyl-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.40-2.53 (2H, m), 2.60 (3H, s),2.68 (3H, s), 2.83 (2H, t, J=7 Hz), 3.03 (2H, q, J=7 Hz), 5.83 (1H, d,J=4 Hz), 6.53 (1H, d, J=4 Hz), 8.27 (1H, m), 8.78 (1H, d, J=2 Hz), 9.22(1H, d, J=2 Hz).

MS (ESI⁻): m/z 350, MS (ESI⁺): m/z 352.

EXAMPLE 3555-[2-[(benzyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.35-1.55 (4H, m), 2.05-2.20 (2H,m), 2.42 (3H, s), 2.40-2.70 (2H, m), 3.03 (2H, q, J=7 Hz), 4.63 (2H, s),4.74 (2H, m), 5.88 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.27-7.42 (5H,m), 7.53 (1H, s), 8.40 (1H, s), 8.53 (1H, s).

MS (ESI⁺): m/z 458.

EXAMPLE 3563-[2-[(benzyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.40 (3H, s), 2.40-2.54 (2H, m),2.80-3.08 (2H, m), 3.06 (2H, q, J=7 Hz), 4.65 (2H, s), 4.77 (2H, m),5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.26-7.42 (5H, m), 7.54 (1H,s), 8.39 (1H, d, J=2 Hz), 8.48 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 428, MS (ESI⁺): m/z 430.

EXAMPLE 3575-[2-[(cyclohexyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.20-1.45 (6H, m), 1.36 (3H, t, J=7 Hz), 1.45-1.63 (4H,m), 1.70-1.83 (2H, m), 1.95-2.08 (2H, m), 2.14-2.28 (2H, m), 2.42 (3H,s), 2.46-2.60 (1H, m), 2.60-2.75 (1H, m), 3.03 (2H, q, J=7 Hz),3.42-3.54 (1H, m), 4.72 (2H, m), 5.87 (1H, d, J=4 Hz), 6.54 (1H, d, J=4Hz), 7.55 (1H, s), 8.41 (1H, s), 8.53 (1H, s).

MS (ESI⁻): m/z 448, MS (ESI⁺): m/z 450.

EXAMPLE 3585-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.18-1.60 (10H, m), 1.36 (3H, t, J=7 Hz), 1.70-1.80(2H, m), 1.95-2.05 (2H, m), 2.22 (2H, t, J=7 Hz), 2.50-2.70 (2H, m),3.03 (2H, q, J=7 Hz), 3.42-3.53 (1H, m), 4.68 (2H, s), 5.89 (1H, d, J=4Hz), 6.58 (1H, d, J=4 Hz), 7.88 (1H, s), 8.54 (1H, d, J=2 Hz), 8.77 (1H,d, J=2 Hz).

MS (ESI⁺): m/z 514 516.

EXAMPLE 3593-[2-[(cyclohexyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 1.20-1.45 (5H, m), 1.37 (3H, t, J=7 Hz), 1.50-1.60 (1H,m), 1.72-1.84 (2H, m), 1.96-2.08 (2H, m), 2.42 (3H, s), 2.48-2.62 (2H,m), 2.80-3.10 (2H, m), 3.03 (2H, q, J=7 Hz), 3.44-3.66 (1H, m), 4.73(2H, s), 5.88 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.55 (1H, s), 8.40(1H, s), 8.51 (1H, s).

MS (ESI⁺): m/z 422.

EXAMPLE 3603-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexyloxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (CDCl₃) δ 1.18-1.47 (5H, m), 1.37 (3H, t, J=7 Hz), 1.52-1.63 (1H,m), 1.72-1.85 (2H, m), 1.97-2.07 (2H, m), 2.48-2.62 (2H, m), 2.80-3.10(2H, m), 3.03 (2H, q, J=7 Hz), 3.44-3.57 (1H, m), 4.73 (2H, s), 5.91(1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.88 (1H, t, J=2 Hz), 8.55 (1H,d, J=2 Hz), 8.77 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 484 486, MS (ESI⁺): m/z 486 488.

EXAMPLE 3615-[7-ethyl-2-(isopropoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.25 (6H, d, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.44-1.63(4H, m), 2.15-2.27 (2H, m), 2.43 (3H, s), 2.47-2.60 (1H, m), 2.60-2.73(1H, m), 3.03 (2H, q, J=7 Hz), 3.75-3.87 (1H, m), 4.67 (2H, s), 5.87(1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz), 7.55 (1H, s), 8.41 (1H, s), 8.53(1H, s).

MS (ESI⁻): m/z 408, MS (ESI⁺): m/z 410.

EXAMPLE 3625-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isopropoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.25 (6H, d, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.45-1.65(4H, m), 2.23 (2H, t, J=7 Hz), 2.50-2.60 (2H, m), 3.03 (2H, q, J=7 Hz),3.75-3.85 (1H, m), 4.66 (2H, s), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4Hz), 7.89 (1H, m), 8.54 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 474 476.

EXAMPLE 3635-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.40-1.65 (4H, m), 2.22 (2H, t,J=7 Hz), 2.33-2.45 (2H, m), 2.43 (3H, s), 3.03 (2H, q, J=7 Hz), 4.87(2H, s), 5.94 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.56 (1H, s), 8.43(1H, s), 8.54 (1H, s).

MS (ESI⁻): m/z 366, MS (ESI⁺): m/z 368.

EXAMPLE 3645-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[2-(4-morpholinyl)-2-oxoethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.22 (2H, t,J=7 Hz), 2.43 (3H, s), 2.50-2.72 (2H, m), 3.03 (2H, q, J=7 Hz), 3.51(2H, m), 3.57-3.75 (6H, m), 4.32 (2H, s), 4.70-4.86 (2H, m), 5.90 (1H,d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.53 (1H, s), 8.42 (1H, s), 8.53 (1H,s).

MS (ESI): m/z 493, MS (ESI⁺): m/z 495.

EXAMPLE 3655-[7-ethyl-2-{[2-(methylamino)-2-oxoethoxy]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.40-1.65 (4H, m), 2.22 (2H, t,J=7 Hz), 2.44 (3H, s), 2.45-2.64 (2H, m), 2.87 (3H, m), 3.03 (2H, q, J=7Hz), 4.13 (2H, s), 4.74 (2H, m), 5.93 (1H, d, J=4 Hz), 6.60 (1H, d, J=4Hz), 6.83 (1H, br), 7.57 (1H, s), 8.42 (1H, s), 8.53 (1H, s).

MS (ESI⁻): m/z 437, MS (ESI⁺): m/z 439.

EXAMPLE 3665-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 0.23-0.33 (2H, m), 0.55-0.64 (2H, m), 1.07-1.22 (1H,m), 1.36 (3H, t, J=7 Hz), 1.45-1.68 (4H, m), 2.19 (2H, t, J=7 Hz), 2.43(3H, s), 2.50-2.75 (2H, m), 3.02 (2H, q, J=7 Hz), 3.40 (2H, d, J=7 Hz),4.70 (2H, m), 5.87 (1H, d, J=4 Hz), 6.56 (1H, d, J=4 Hz), 7.57 (1H, s),8.40 (1H, s), 8.54 (1H, s).

MS (ESI⁺): m/z 422.

EXAMPLE 3675-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 0.87-1.04 (2H, m), 1.10-1.82 (13H, m), 1.37 (3H, t, J=7Hz), 2.18 (2H, t, J=7 Hz), 2.43 (3H, s), 2.47-2.72 (2H, m), 3.03 (2H, q,J=7 Hz), 3.33 (2H, d, J=7 Hz), 4.63 (2H, m), 5.87 (1H, d, J=4 Hz), 6.56(1H, d, J=4 Hz), 7.56 (1H, s), 8.42 (1H, s), 8.53 (1H, s).

MS (ESI⁻): m/z 462, MS (ESI⁺): m/z 464.

EXAMPLE 3685-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.35-1.57 (4H, m), 2.13 (2H, t,J=7 Hz), 2.42 (3H, s), 2.47-2.66 (2H, m), 3.03 (2H, q, J=7 Hz), 4.68(2H, s), 4.77 (2H, m), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz),7.28-7.36 (1H, m), 7.53 (1H, s), 7.73 (1H, d, J=8 Hz), 8.41 (1H, d, J=2Hz), 8.53 (2H, m), 8.63 (1H, s).

MS (ESI⁻): m/z 457, MS (ESI⁺): m/z 459.

EXAMPLE 3695-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.23 (2H, t,J=7 Hz), 2.41 (3H, s), 2.48-2.74 (2H, m), 3.03 (2H, q, J=7 Hz), 4.80(2H, s), 4.82 (2H, m), 5.88 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.26(1H, m), 7.47-7.53 (2H, m), 7.69-7.77 (1H, m), 8.42 (1H, d, J=2 Hz),8.50 (1H, d, J=2 Hz), 8.58 (1H, d, J=7 Hz).

MS (ESI⁻): m/z 457, MS (ESI⁺): m/z 459.

EXAMPLE 3705-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.16 (2H, t,J=7 Hz), 2.43 (3H, s), 2.48-2.71 (2H, m), 3.02 (2H, q, J=7 Hz), 4.68(2H, s), 4.79 (2H, m), 5.91 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.32(2H, d, J=7 Hz), 7.54 (1H, s), 8.42 (1H, d, J=2 Hz), 8.54 (1H, d, J=2Hz), 8.55 (2H, d, J=7 Hz).

MS (ESI⁻): m/z 457, MS (ESI⁺): m/z 459.

EXAMPLE 3715-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.45-1.62 (4H, m), 2.18 (2H, t,J=7 Hz), 2.43 (3H, s), 2.48-2.73 (2H, m), 3.03 (2H, q, J=7 Hz), 4.83(2H, s), 4.88 (2H, m), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.54(1H, s), 8.42 (1H, s), 8.48-8.56 (3H, m), 8.76 (1H, s).

MS (ESI⁻): m/z 458, MS (ESI⁺): m/z 460.

EXAMPLE 3725-[2-[(benzylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (DMSO-d₆) δ 1.33 (3H, t, J=7 Hz), 1.28-1.48 (4H, m), 2.03-2.13(2H, m), 2.30-2.45 (2H, m), 2.40 (3H, s), 3.06 (2H, q, J=7 Hz), 4.37(2H, s), 4.46 (2H, s), 5.92 (1H, d, J=4 Hz), 6.68 (1H, d, J=4 Hz),7.40-7.52 (3H, m), 7.56-7.67 (3H, m), 8.36 (1H, d, J=2 Hz), 8.57 (1H, d,J=2 Hz).

MS (ESI⁺): m/z 457.

EXAMPLE 3735-[2-[(acetylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.40 (3H, t, J=7 Hz), 1.40-1.64 (4H, m), 2.16 (3H, s),2.23 (2H, t, J=7 Hz), 2.35-2.50 (2H, m), 2.43 (3H, s), 3.03 (2H, q, J=7Hz), 4.63-4.72 (2H, m), 5.92 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz),6.88-6.97 (1H, br), 7.53 (1H, s), 8.41 (1H, s), 8.53 (1H, s).

MS (ESI⁻): m/z 407, MS (ESI⁺): m/z 409.

EXAMPLE 3745-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(methylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.46-1.66 (4H, m), 2.23 (2H, t,J=7 Hz), 2.44 (3H, s), 2.39-2.53 (2H, m), 3.03 (2H, q, J=7 Hz), 3.05(3H, s), 4.57 (2H, s), 5.72 (1H, br), 5.96 (1H, d, J=4 Hz), 6.61 (1H, d,J=4 Hz), 7.54 (1H, s), 8.41 (1H, d, J=2 Hz), 8.55 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 443, MS (ESI⁺): m/z 445.

EXAMPLE 3755-[2-[(benzoylamino)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.42 (3H, t, J=7 Hz), 1.50-1.68 (4H, m), 2.25 (2H, t,J=7 Hz), 2.44 (3H, s), 2.40-2.60 (2H, m), 3.07 (2H, q, J=7 Hz), 4.89(2H, m), 5.95 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.46-7.60 (4H, m),7.83 (1H, br), 7.93 (2H, d, J=8 Hz), 8.44 (1H, d, J=2 Hz), 8.56 (1H, d,J=2 Hz).

MS (ESI⁻): m/z 469, MS (ESI⁺): m/z 471.

EXAMPLE 3765-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(2-pyrazinylcarbonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoicacid

¹H NMR (CDCl₃) δ 1.41 (3H, t, J=7 Hz), 1.51-1.72 (4H, m), 2.24 (2H, t,J=7 Hz), 2.44 (3H, s), 2.45-2.58 (2H, m), 3.10 (2H, q, J=7 Hz), 4.90(2H, m), 5.94 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.55 (1H, s), 8.43(1H, s), 8.53 (1H, s), 8.62 (1H, m), 8.79 (1H, d, J=2 Hz), 9.20 (1H,br), 9.45 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 471, MS (ESI⁺): m/z 473.

EXAMPLE 3775-[7-ethyl-2-{[(methoxycarbonyl)amino]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.23 (2H, t,J=7 Hz), 2.40-2.53 (2H, m), 2.44 (3H, s), 3.02 (2H, q, J=7 Hz), 3.05(3H, s), 4.58 (2H, s), 5.69 (1H, br), 5.96 (1H, d, J=4 Hz), 6.61 (1H, d,J=4 Hz), 7.53 (1H, s), 8.41 (1H, d, J=2 Hz), 8.54 (1H, d, J=2 Hz).

EXAMPLE 378

To a solution of ethyl7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylate(682 mg) in ethanol (20 mL) was added potassium hydroxide (5 g) solution(10 mL) and the mixture was heated under reflux for 1 hour. The solutionwas acidified with 1 N hydrochloric acid to pH 3-4 and diluted withbrine, and extracted with chloroform twice. The organic layer wasseparated, dried over magnesium sulfate, and evaporated in vacuo. Thecrude produt was triturated with ethyl acetate to give7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylicacid as a yellow powder (590 mg)

7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylicacid

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=7 Hz), 2.44 (3H, s), 2.69 (3H, s), 3.05(2H, q, J=7 Hz), 6.29 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.97 (1H,s), 8.41 (1H, s), 8.58 (1H, s).

MS (ESI⁻): m/z 294, MS (ESI⁺): m/z 296.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 175.

EXAMPLE 3795-[4-(3-cyanophenyl)-2-(ethoxymethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.34-1.53 (7H, m), 2.20 (2H, t,J=7 Hz), 2.53 (2H, m), 3.03 (2H, q, J=7 Hz), 3.62 (2H, q, J=7 Hz), 4.66(2H, s), 5.33 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.60 (2H, m), 7.66(1H, s), 7.74 (1H, m)

EXAMPLE 3805-[2-[(benzyloxy)methyl]-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.30-1.46 (7H, m), 2.11 (2H, t, J=7 Hz), 2.50 (2H, m),3.02 (2H, q, J=7 Hz), 4.64 (3H, s), 4.71 (3H, s), 5.83 (1H, d, J=5 Hz),6.56 (1H, d, J=5 Hz), 7.25-7.34 (5H, m), 7.57 (2H, d, J=9 Hz), 7.65 (1H,s), 7.74 (1H, m).

MS (ESI⁺): m/z 468 (M+H)

EXAMPLE 3814-({[3-(4-carboxybutyl)-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methoxy}methyl)benzoicacid

¹H-NMR (CDCl₃) δ 1.05-1.43 (7H, m), 1.92 (2H, m), 2.31 (2H, m), 3.04(2H, m), 4.65 (2H, s), 4.72 (2H, s), 5.82 (1H, m), 6.58 (1H, m),7.46-7.77 (6H, m), 8.09 (2H, d, J=8 Hz).

MS (ESI⁺): m/z 510 (M−H)

EXAMPLE 381-24-({[4-[3-(carbamoyl)phenyl]-3-(4-carboxybutyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methoxy}methyl)benzoicacid

¹H-NMR (CDCl₃) δ 1.20-1.45 (7H, m), 2.03 (2H, m), 2.52 (2H, m), 3.03(2H, q, J=7 Hz), 4.69 (2H, s), 4.73 (2H, s), 5.36 (1H, d, J=5 Hz), 6.57(1H, d, J=5 Hz), 7.39-7.60 (4H, m), 7.77 (1H, s), 7.93 (1H, d, J=8 Hz),7.98 (2H, d, J=8 Hz).

MS (ESI⁺): m/z 528 (M−H)

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 77.

EXAMPLE 3825-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-methyl-1-piperazinyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.34 (3H, t, J=7 Hz), 1.38-1.59 (4H, m), 2.22 (2H, m),2.43-2.60 (5H, m), 2.83-3.04 (8H, m), 3.74 (3H, s), 5.88 (1H, d, J=5Hz), 6.56 (1H, d, J=5 Hz), 7.87 (1H, m), 8.54 (1H, m), 8.76 (1H, m).

EXAMPLE 3835-[4-(5-bromo-3-pyridinyl)-2-(cyanomethyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.35-1.60 (7H, m), 2.27 (2H, m), 2.46 (2H, m), 3.03(2H, q, J=7 Hz), 3.98 (2H, s), 3.97 (1H, d, J=5 Hz), 6.65 (1H, d, J=5Hz), 7.90 (1H, m), 8.54 (1H, s, br), 8.79 (1H, s, br).

EXAMPLE 3845-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.35-1.60 (7H, m), 2.22 (2H, t, J=7 Hz), 2.38 (2H, m),3.02 (2H, q, J=7 Hz), 4.86 (2H, s), 5.95 (1H, d, J=5 Hz), 6.60 (1H, d,J=5 Hz), 7.88 (1H, m), 8.54 (1H, s, br), 8.79 (1H, s, br).

EXAMPLE 385

To a solution of7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylicacid (70 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimidehydrochloride (68.2 mg) and 1-hydroxybenotriazole (48 mg) indimethylformamide (2 mL) was added 2-aminoethanol (17.4 mg) and themixture was stirred at ambient temperature for 1 hour. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with saturated sodium bicarbonate solution, water andbrine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was purified by silica gel column chromatography eluting with amixture of chloroform and methanol (50:1-10:1). The crude product wastriturated with isopropylether to give7-ethyl-N-(2-hydroxyethyl)-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxamideas a yellow powder (47 mg).

7-ethyl-N-(2-hydroxyethyl)-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxamide

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.39 (3H, s), 2.57 (3H, s), 3.02(2H, q, J=7 Hz), 3.33 (2H, m), 3.45 (2H, m), 6.03 (1H, br), 6.31 (1H, d,J=4 Hz), 6.66 (1H, d, J=4 Hz), 7.71 (1H, s), 8.47 (1H, s), 8.58 (1H, s).

MS (ESI⁻): m/z 337, MS (ESI⁺): m/z 339.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 385.

EXAMPLE 386N-butyl-7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxamide

¹H NMR (CDCl₃) δ 0.80 (3H, t, J=7 Hz), 0.96-1.08 (2H, m), 1.08-1.25 (2H,m), 1.38 (3H, t, J=7 Hz), 2.40 (3H, s), 2.56 (3H, s), 3.03 (2H, q, J=7Hz), 3.16 (2H, m), 5.36 (1H, br), 6.31 (1H, d, J=4 Hz), 6.63 (1H, d, J=4Hz), 7.69 (1H, s), 8.53 (1H, s), 8.62 (1H, s).

MS (ESI⁺): m/z 351.

EXAMPLE 387 ethyl3-({[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]carbonyl}amino)propanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.21 (2H,t, J=7 Hz), 2.40 (3H, s), 2.55 (3H, s), 3.03 (2H, q, J=7 Hz), 3.43 (2H,q, J=7 Hz), 4.04 (2H, q, J=7 Hz), 6.08 (1H, br), 6.30 (1H, d, J=4 Hz),6.65 (1H, d, J=4 Hz), 7.67 (1H, s), 8.50 (1H, d, J=1 Hz), 8.60 (1H, d,J=1 Hz).

MS (ESI⁺): m/z 395.

The following compound(s) was (were) obtained in substantially the samemanner as that of Preparation 176.

EXAMPLE 3884-(5-bromo-3-pyridinyl)-7-ethyl-2-methyl-3-[3-(4-morpholinyl)-3-oxopropyl]pyrrolo[1,2-b]pyridazine

¹H NMR(CDCl₃) δ: ¹H NMR(CDCl₃) δ: 1.37(3H, t, J=7 Hz), 2.41(2H, t, J=7Hz), 2.60(3H, s), 2.72-2.82(2H, m), 3.01(2H, q, J=7 Hz), 3.19(2H, t, J=5Hz), 3.55(4H, t, J=5 Hz), 3.63(2H, t, J=5 Hz), 5.89(1H, d, J=4 Hz),6.55(1H, d, J=4 Hz), 7.87(1H, t, J=1 Hz), 8.54(1H, d, J=1 Hz), 8.77(1H,d, J=1 Hz)

MS (m/z) 457(M⁺), 459(M++2), 115(bp)

mp. 178-180° C.

EXAMPLE 3893-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-N-methylpropanamide

¹H NMR(CDCl₃) δ: ¹H NMR(CDCl₃) δ: 1.38(3H, t, J=7 Hz), 2.20(2H, t, J=7Hz), 2.60(3H, s), 2.75(3H, d, J=6 Hz), 2.78-2.89(2H, m), 3.01(2H, q, J=7Hz), 5.21-5.27(1H, m), 5.88(1H, d, J=4 Hz), 6.54(1H, d, J=4 Hz),7.86(1H, t, J=1 Hz), 8.53(1H, d, J=1 Hz), 8.78(1H, d, J=1 Hz),

MS (m/z) 401(M⁺+1), 403(M⁺+1), 115(bp)

mp. 172-174° C.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 263.

EXAMPLE 390N-{3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoyl}methanesulfonamide

¹H NMR(CDCl₃) δ: 1.36(3H, t, J=7 Hz), 2.33-2.45(2H, m), 2.58(3H, s),2.84-2.95(2H, m), 3.01(2H, q, J=7 Hz), 3.26(3H, s), 5.89(1H, d, J=4 Hz),6.56(1H, d, J=4 Hz), 7.90(1H, s), 8.50(1H, s), 8.77(1H, s)

MS (m/z) 465(M+, bp), 467(M⁺−2, bp)

mp. 196.5-197.5° C.

The following compound(s) was (were) obtained in substantially the samemanner as that of Example 224.

EXAMPLE 3912-[{3-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoyl}(methyl)amino]ethanesulfonicacid

¹H NMR (CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.90 2H, m), 2.26 (3H, s),2.57-2.2.78 (4H, m), 2.98 (2H, q, J=7 Hz), 3.31 (2H, m), 6.00 (1H, d,J=5 Hz), 6.61 (1H, d, J=5 Hz), 7.20-7.52 (5H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 20.

Preparation 217

1-tert-butyl 7-ethyl 2-(isobutoxyacetyl)heptanedioate

¹H NMR (300 MHz, CDCl₃) δ 0.95 (6H, d, J=7 Hz), 1.27 (3H, t, J=7 Hz),1.31-1.41 (2H, m), 1.46 (9H, s), 1.66 (2H, tt, J=7, 7 Hz), 1.75-1.98(3H, m), 2.31 (2H, t, J=8 Hz), 3.26 (2H, d, J=7 Hz), 3.56 (1H, t, J=7Hz), 4.06-4.17 (4H, m).

Preparation 218

1-tert-butyl 6-ethyl 2-(isobutoxyacetyl)hexanedioate

¹H NMR (300 MHz, CDCl₃) δ 0.93 (6H, d, J=7 Hz), 1.25 (3H, t, J=7 Hz),1.45 (9H, s), 1.59-1.69 (2H, m), 1.80-1.95 (3H, m), 2.32 (2H, t, J=7Hz), 2.25 (2H, d, J=7 Hz), 3.57 (1H, t, J=7 Hz), 4.10 (2H, s), 4.12 (2H,q, J=7 Hz).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 24.

Preparation 219

1-tert-butyl 6-ethyl 2-acetyl-2-(2-chloroisonicotinoyl)hexanedioate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.34 (9H, s), 1.60-1.73 (2H, m),2.22-2.32 (2H, m), 2.39 (2H, t, J=7 Hz), 2.49 (3H, s), 4.12 (2H, q, J=7Hz), 7.43 (1H, d, J=5 Hz), 7.57 (1H, s), 8.50 (1H, d, J=5 Hz).

MS (ESI⁺): m/z 412.

Preparation 220

1-tert-butyl 5-ethyl 2-acetyl-2-(2-chloroisonicotinoyl)pentanedioate

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.72-1.84 (2H, m), 2.33 (2H, t,J=7 Hz), 2.47-2.57 (2H, m), 2.58 (3H, s), 3.03 (2H, q, J=7 Hz), 5.88(1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.27 (1H, m), 7.38 (1H, s), 8.53(1H, d, J=5 Hz).

MS (ESI⁻): m/z 356, MS (ESI⁺): m/z 358.

Preparation 221

1-tert-butyl 7-ethyl2-(2-chloroisonicotinoyl)-2-(phenylacetyl)heptanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.35 (9H, s), 1.63-1.76 (2H, m),2.22-2.37 (4H, m), 3.93 (1H, d, J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.29(1H, d, J=17 Hz), 7.22 (2H, d, J=8 Hz), 7.26-7.36 (4H, m), 7.50 (1H, s),8.42 (1H, d, J=5 Hz).

MS (ESI⁺): m/z 502.

Preparation 222

tert-butyl2-[2-(2-methoxy-2-oxoethoxy)ethyl]-2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate

¹H NMR (CDCl₃) δ 1.33 (9H, s), 2.39 (3H, s), 2.47 (3H, s), 2.62 (2H, t,J=7 Hz), 3.66 (2H, m), 3.70 (3H, s), 3.90 (2H, s), 7.87 (1H, s), 8.56(1H, s), 8.75 (1H, s).

MS (ESI⁺): m/z 394.

Preparation 223

1-tert-butyl 4-ethyl 2-acetyl-2-[(5-bromo-3-pyridinyl)carbonyl]succinate

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=7 Hz), 1.41 (9H, s), 2.45 (3H, s), 3.22(2H, m), 4.12 (2H, q, J=7 Hz), 8.22 (1H, m), 8.80 (1H, m), 8.82 (1H, m).

MS (ESI⁺): m/z 428 430.

Preparation 224

1-tert-butyl 5-ethyl2-[(acetyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.35 (9H, s), 2.14 (3H, s), 2.40(3H, s), 2.40-2.48 (2H, m), 2.62-2.70 (2H, m), 4.12 (2H, q, J=7 Hz),5.12 (1H, d, J=18 Hz), 5.34 (1H, d, J=18 Hz), 7.85 (1H, s), 8.58 (1H,s), 8.78 (1H, s).

MS (ESI⁺): m/z 436.

Preparation 225

1-tert-butyl 6-ethyl2-[(acetyloxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.34 (9H, s), 1.60-1.75 (2H, m),2.14 (3H, s), 2.26-2.39 (4H, m), 2.40 (3H, s), 4.12 (2H, q, J=7 Hz),5.13 (1H, d, J=18 Hz), 5.40 (1H, d, J=18 Hz), 7.86 (1H, s), 8.57 (1H,s), 8.78 (1H, s).

MS (ESI⁺): m/z 450.

Preparation 226

1-tert-butyl 7-ethyl2-[(acetyloxy)acetyl]-2-(3-cyanobenzoyl)heptanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.32 (9H, s), 1.26-1.46 (2H, m),1.66-1.77 (2H, m), 2.14 (3H, s), 2.26-2.38 (4H, m), 4.12 (2H, q, J=7Hz), 5.06 (1H, d, J=18 Hz), 5.42 (1H, d, J=18 Hz), 7.57 (1H, t, J=8 Hz),7.81 (1H, d, J=8 Hz), 7.92 (1H, d, J=8 Hz), 8.09 (1H, s).

Preparation 227

1-tert-butyl 6-ethyl2-[(acetyloxy)acetyl]-2-[(5-bromo-3-pyridinyl)carbonyl]hexanedioate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.36 (9H, s), 1.60-1.74 (2H, m),1.85-1.96 (2H, m), 2.14 (3H, s), 2.28-2.42 (2H, m), 4.12 (2H, q, J=7Hz), 5.12 (1H, d, J=17 Hz), 5.42 (1H, d, J=17 Hz), 8.23 (1H, m), 8.81(1H, m), 8.83 (1H, m).

Preparation 228

1-tert-butyl 5-ethyl2-[(acetyloxy)acetyl]-2-[(5-bromo-3-pyridinyl)carbonyl]pentanedioate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.37 (9H, s), 2.14 (3H, s),2.41-2.51 (2H, m), 2.66 (2H, t, J=7 Hz), 4.13 (2H, q, J=7 Hz), 5.11 (1H,d, J=18 Hz), 5.33 (1H, d, J=18 Hz), 8.22 (1H, m), 8.82 (2H, m).

MS (ESI⁺): m/z 500 502.

Preparation 229

1-tert-butyl 5-ethyl2-[(cyclohexylmethoxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate

¹H NMR (CDCl₃) δ 0.80-0.98 (2H, m), 1.00-1.32 (3H, m), 1.23 (3H, t, J=7Hz), 1.38 (9H, s), 1.46-1.62 (6H, m), 2.39 (3H, s), 2.40-2.72 (4H, m),3.19 (2H, d, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.31 (1H, d, J=17 Hz), 4.39(1H, d, J=17 Hz), 7.88 (1H, s), 8.56 (1H, s), 8.77 (1H, s).

MS (ESI⁺): m/z 490.

Preparation 230

1-tert-butyl 5-ethyl2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(cyclohexylmethoxy)acetyl]pentanedioate

¹H NMR (CDCl₃) δ 0.78-0.98 (2H, m), 1.10-1.33 (3H, m), 1.25 (3H, t, J=7Hz), 1.40 (9H, s), 1.38-1.83 (6H, m), 2.35-2.75 (4H, m), 3.22 (2H, d,J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.25 (1H, d, J=17 Hz), 4.37 (1H, d, J=17Hz), 8.22 (1H, s), 8.78 (1H, s), 8.86 (1H, s).

MS (ESI⁺): m/z 554 556.

Preparation 231

1-tert-butyl 6-ethyl2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(cyclohexylmethoxy)acetyl]hexanedioate

¹H NMR (CDCl₃) δ 0.80-0.97 (2H, m), 1.12-1.35 (3H, m), 1.25 (3H, t, J=7Hz), 1.39 (9H, s), 1.46-1.80 (10H, m), 2.22-2.45 (2H, m), 3.20 (2H, d,J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.30 (1H, d, J=17 Hz), 4.38 (1H, d, J=17Hz), 8.22 (1H, s), 8.78 (1H, s), 8.85 (1H, s).

MS (ESI⁺): m/z 568 570.

Preparation 232

1-tert-butyl 6-ethyl2-[(cyclopropylmethoxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]hexanedioate

¹H NMR (CDCl₃) δ 0.16-0.28 (2H, m), 0.48-0.59 (2H, m), 0.98-1.12 (1H,m), 1.24 (3H, t, J=7 Hz), 1.37 (9H, s), 1.55-1.80 (4H, m), 2.18-2.40(2H, m), 2.39 (3H, s), 3.31 (2H, m), 4.12 (2H, q, J=7 Hz), 4.38 (1H, d,J=17 Hz), 4.53 (1H, d, J=17 Hz), 7.88 (1H, s), 8.55 (1H, d, J=2 Hz),8.75 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 462.

Preparation 233

1-tert-butyl 5-ethyl2-[(cyclopropylmethoxy)acetyl]-2-[(5-methyl-3-pyridinyl)carbonyl]pentanedioate

¹H NMR (CDCl₃) δ 0.15-0.23 (2H, m), 0.48-0.56 (2H, m), 0.95-1.10 (1H,m), 1.24 (3H, t, J=7 Hz), 1.39 (9H, s), 2.39 (3H, s), 2.40-2.68 (4H, m),3.28 (2H, m), 4.12 (2H, q, J=7 Hz), 4.36 (1H, d, J=17 Hz), 4.48 (1H, d,J=17 Hz), 7.88 (1H, s), 8.55 (1H, s), 8.75 (1H, s).

MS (ESI⁺): m/z 448.

Preparation 234

1-tert-butyl 5-ethyl2-[(5-bromo-3-pyridinyl)carbonyl]-2-[(2-methoxyethoxy)acetyl]pentanedioate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.46 (9H, s), 2.15-2.25 (2H, m),2.42-2.72 (2H, m), 3.38 (3H, s), 3.48-3.72 (4H, m), 4.12 (2H, q, J=7Hz), 4.43 (1H, d, J=17 Hz), 4.58 (1H, d, J=17 Hz), 8.22 (1H, s), 8.78(1H, s), 8.82 (1H, s).

MS (ESI⁺): m/z 516 518.

Preparation 235

tert-butyl 2-[(5-bromo-3-pyridinyl)carbonyl]-3-oxobutanoate

¹H NMR (CDCl₃) δ 1.22, 1.30 (9H, s), 2.22, 2.45 (3H, s), 7.96, 8.13 (1H,s), 8.66, 8.76-8.80 (2H, m).

Preparation 236

1-tert-butyl 6-ethyl2-[(acetyloxy)acetyl]-2-[(5-chloro-3-pyridinyl)carbonyl]hexanedioate

¹H NMR (300 MHz, CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.36 (9H, s), 1.63-1.71(2H, m), 2.14 (3H, s), 2.27-2.40 (4H, m), 4.13 (2H, q, J=7 Hz), 5.11(1H, d, J=18 Hz), 5.38 (1H, d, J=18 Hz), 8.07 (1H, dd, J=2 Hz), 8.71(1H, d, J=2 Hz), 8.80 (1H, d, J=2 Hz).

Preparation 237

1-tert-butyl 7-ethyl2-[(5-chloro-3-pyridinyl)carbonyl]-2-[(cyclopropylmethoxy)acetyl]heptanedioate

¹H NMR (300 MHz, CDCl₃) δ 0.15-0.20 (2H, m), 0.49-0.58 (2H, m),0.95-1.04 (1H, m), 1.24 (3H, t, J=7 Hz), 1.38 (9H, s), 1.68 (2H, tt,J=7, 7 Hz), 2.14-2.33 (4H, m), 3.26-3.29 (2H, m), 4.07-4.19 (4H, m),4.31 (1H, d, J=17 Hz), 4.45 (1H, d, J=17 Hz), 8.05 (1H, dd, J=2 Hz),8.68 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

Preparation 238

1-tert-butyl 6-ethyl2-[(5-chloro-3-pyridinyl)carbonyl]-2-[(cyclopropylmethoxy)acetyl]hexanedioate

¹H NMR (300 MHz, CDCl₃) δ 0.14-0.21 (2H, m), 0.49-0.55 (2H, m),0.92-1.04 (1H, m), 1.25 (3H, t, J=7 Hz), 1.39 (9H, s), 1.62-1.74 (2H,m), 1.82-1.90 (2H, m), 2.21-2.33 (2H, m), 3.27-3.31 (2H, m), 4.12 (2H,q, J=7 Hz), 4.34 (1H, d, J=18 Hz), 4.46 (1H, d, J=18 Hz), 8.07 (1H, dd,J=2, 2 Hz), 8.68 (1H, d, J=2 Hz), 8.80 (1H, d, J=2 Hz).

Preparation 239

1-tert-butyl 7-ethyl2-[(5-bromo-3-pyridinyl)carbonyl]-2-(isobutoxyacetyl)heptanedioate

¹H NMR (300 MHz, CDCl₃) δ 0.85 (6H, d, J=7 Hz), 1.24 (3H, t, J=7 Hz),1.38 (9H, s), 1.67 (2H, t, J=7 Hz), 1.75-1.93 (3H, m), 2.24-2.33 (4H,m), 3.17 (2H, d, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.28 (1H, d, J=17 Hz),4.38 (1H, d, J=17 Hz), 8.20 (1H, dd, J=2, 2 Hz), 8.79 (1H, d, J=2 Hz),8.84 (1H, d, J=2 Hz).

Preparation 240

1-tert-butyl 5-ethyl2-[(5-chloro-3-pyridinyl)carbonyl]-2-(isobutoxyacetyl)pentanedioate

¹H NMR (300 MHz, CDCl₃) δ 0.84 (6H, d, J=7 Hz), 1.24 (3H, t, J=7 Hz),1.39 (9H, s), 1.80 (1H, qt, J=7 Hz), 2.34-2.71 (4H, m), 3.17 (2H, d, J=7Hz), 4.12 (2H, q, J=7 Hz), 4.28 (1H, d, J=18 Hz), 4.36 (1H, d, J=18 Hz),8.07 (1H, s), 8.69 (1H, s), 8.83 (1H, s).

Preparation 241

1-tert-butyl 5-ethyl2-[(acetyloxy)acetyl]-2-(3-chlorobenzoyl)pentanedioate

¹H NMR (300 MHz, CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.34 (9H, s), 2.14 (3H,s), 2.35-2.44 (2H, m), 2.60-2.68 (2H, m), 4.11 (2H, q, J=7 Hz), 5.11(1H, d, J=18 Hz), 5.35 (1H, d, J=18 Hz), 7.38 (1H, dd, J=8, 8 Hz), 7.53(1H, d, J=8 Hz), 7.60 (1H, d, J=8 Hz), 7.79 (1H, s).

Preparation 242

1-tert-butyl 6-ethyl2-[(5-bromo-3-pyridinyl)carbonyl]-2-(isobutoxyacetyl)hexanedioate

¹H NMR (300 MHz, CDCl₃) δ 0.85 (6H, d, J=7 Hz), 1.25 (3H, t, J=7 Hz),1.39 (9H, s), 1.59-1.72 (2H, m), 1.80 (1H, qt, J=7, 7 Hz), 2.19-2.39(4H, m), 3.18 (2H, d, J 7 Hz), 4.12 (2H, q, J=7 Hz), 4.31 (1H, d, J=17Hz), 4.40 (1H, d, J=17 Hz), 8.22(1H, dd, J=2, 2 Hz), 8.79(1H, d, J=2Hz), 8.85(1H, d, J=2 Hz).

Preparation 243

tert-butyl3-(5-bromo-3-pyridinyl)-2-[(5-bromo-3-pyridinyl)carbonyl]-3-oxopropanoate

¹H NMR (CDCl₃) δ 1.05 (9H, s), 7.86 (2H, s), 8.46 (2H, s), 8.61 (2H, s).

MS (ESI⁻): m/z 481 483 485.

Preparation 244

1-tert-butyl 6-ethyl2-[(acetyloxy)acetyl]-2-(3-chlorobenzoyl)hexanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=8 Hz), 1.33 (9H, s), 1.56-1.72 (2H, m),2.15 (3H, s), 2.20-2.41 (4H, m), 4.11 (2H, q, J=8 Hz), 5.13 (1H, d, J=18Hz), 5.40 (1H, d, J=18 Hz), 738(1H, t, J=8 Hz), 752(1H, br d, J=8 Hz),7.60 (1H, br d, J=8 Hz), 7.79 (1H, br s).

Preparation 245

b 1-tert-butyl 7-ethyl2-(methoxyacetyl)-2-[(5-methoxy-3-pyridinyl)carbonyl]heptanedioate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=8 Hz), 1.27-1.43 (11H, m), 1.60-1.74(2H, m), 2.15-2.34 (4H, m), 3.37 (3H, s), 3.90 (3H, s), 4.10 (2H, q, J=8Hz), 4.35 (1H, d, J=18 Hz), 4.48 (1H, d, J=18 Hz), 7.58 (1H, m), 8.43(1H, d, J=3 Hz), 8.50 (1H, d, J=1 Hz).

MS (ESI⁺): m/z 452 (M+H).

Preparation 246

1-tert-butyl 7-ethyl2-acetyl-2-[(5-methoxy-3-pyridinyl)carbonyl]heptanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=8 Hz), 1.27-1.40 (11H, m), 1.60-1.74(2H, m), 2.15-2.34 (4H, m), 2.44 (3H, s), 3.89 (3H, s), 4.10 (2H, q, J=8Hz), 7.61 (1H, m), 8.43 (1H, d, J=3 Hz), 8.49 (1H, d, J=1 Hz).

MS (ESI⁺): m/z 422 (M+H).

Preparation 247

1-tert-butyl 5-ethyl2-(methoxyacetyl)-2-[(5-methoxy-3-pyridinyl)carbonyl]pentanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=8 Hz), 1.38 (9H, s), 2.36-2.48 (2H, m),2.53-2.67 (2H, m), 3.37 (3H, s), 3.90 (3H, s), 4.11 (2H, q, J=8 Hz),4.33 (1H, d, J=18 Hz), 4.45 (1H, d, J=18 Hz), 7.59 (1H, m), 8.43 (1H, d,J=3 Hz), 8.51 (1H, d, J=1 Hz).

MS (ESI⁺): m/z 446 (M++Na).

Preparation 248

1-tert-butyl 6-ethyl2-(methoxyacetyl)-2-[(5-methoxy-3-pyridinyl)carbonyl]hexanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=8 Hz), 1.37 (9H, s), 1.52-1.75 (2H, m),2.18-2.39 (4H, m), 3.38 (3H, s), 3.90 (3H, s), 4.11 (2H, q, J=8 Hz),4.37 (1H, d, J=18 Hz), 4.51 (1H, d, J=18 Hz), 7.60 (1H, m), 8.43 (1H, d,J=3 Hz), 8.50 (1H, d, J=1 Hz).

MS (ESI⁺): m/z 438 (M+H).

Preparation 249

1-tert-butyl 7-ethyl2-(methoxyacetyl)-2-(5-pyrimidinylcarbonyl)heptanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=8 Hz), 1.30-1.44 (11H, m), 1.62-1.75(2H, m), 2.16-2.35 (4H, m), 3.35 (3H, s), 4.11 (2H, q, J=8 Hz), 4.20(1H, d, J=18 Hz), 4.33 (1H, d, J=18 Hz), 9.01 (2H, s), 9.31 (1H, s).

MS (ESI⁺): m/z 423 (M+H).

Preparation 250

1-tert-butyl 6-ethyl2-[(5-chloro-3-pyridinyl)carbonyl]-2-(methoxyacetyl)hexanedioate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=8 Hz), 1.39 (9H, s), 1.57-1.74 (2H, m),1.78 (2H, br t, J=8 Hz), 2.23-2.41 (2H, m), 3.38 (3H, s), 4.14 (2H, q,J=8 Hz), 4.33 (1H, d, J=18 Hz), 4.45 (1H, d, J=18 Hz), 8.07 (1H, m),8.71 (1H, br s), 8.80 (1H, br s).

MS (ESI⁺): m/z 442 (M+H).

Preparation 251

1-tert-butyl 5-ethyl2-[(5-chloro-3-pyridinyl)carbonyl]-2-(methoxyacetyl)pentanedioate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=8 Hz), 1.39 (9H, s), 2.37-2.48 (2H, m),2.53-2.65 (2H, m), 3.36 (3H, s), 4.13 (2H, q, J=8 Hz), 4.26 (1H, d, J=18Hz), 4.40 (1H, d, J=18 Hz), 8.06 (1H, br s), 8.70 (1H, br s), 8.80 (1H,br s).

MS (ESI⁺): m/z 428 (M+H).

Preparation 252

1-tert-butyl 7-ethyl2-[(5-chloro-3-pyridinyl)carbonyl]-2-(methoxyacetyl)heptanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=8 Hz), 1.31-1.48 (11H, m), 1.55-1.75(2H, m), δ 2.15-2.35 (4H, m), 3.36 (3H, s), 4.10 (2H, q, J=8 Hz), 4.27(1H, d, J=18 Hz), 4.43 (1H, d, J=18 Hz), 8.03 (1H, t, J=2 Hz), 8.69 (1H,d, J=2 Hz), 8.77 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 456 (M+H).

Preparation 253

methyl 4-(acetyloxy)-2-[(5-bromo-3-pyridinyl)carbonyl]-3-oxobutanoate

¹H NMR (CDCl₃) δ 2.21 (3H, s), 3.58 (3H, br s), 4.87 (1H, br s), 5.19(2H, br s), 7.98 (1H, br s), 8.58 (1H, br s), 8.79 (1H, br s).

MS (ESI⁺): m/z 358, 360 (M+H).

Preparation 254

tert-butyl2-(2-{2-[2-(acetyloxy)ethoxy]ethoxy}ethyl)-2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate

¹H-NMR (CDCl₃) δ 1.32 (9H, s), 2.07 (3H, s), 2.38 (3H, s), 2.45 (3H, s),2.57 (2H, t, J=7 Hz), 3.43 (4H, m), 3.57 (4H, m), 4.16 (2H, m), 7.84(1H, m), 8.53 (1H, m), 8.75 (1H, m).

Preparation 255

1-tert-butyl 6-ethyl2-[(5-bromo-3-pyridinyl)carbonyl]-2-(methoxyacetyl)hexanedioate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.39 (9H, s), 1.55-1.75 (2H, m),2.23-2.45 (4H, m), 3.38 (3H, s), 4.12 (2H, q, J=7 Hz), 4.34 (1H, d, J=18Hz), 4.47 (1H, d, J=18 Hz), 8.22 (1H, m), 8.81 (1H, d, J=2 Hz), 8.83(1H, d, J=2 Hz).

MS (ESI⁺): m/z 486 488.

Preparation 256

ethyl 2-(2-chloroisonicotinoyl)-3-oxobutanoate

¹H NMR (CDCl₃) δ 0.91-1.00 (3H, m), 2.24 (1.2H, s), 2.48 (1.8H, s), 4.02(1.2H, q, J=8 Hz), 4.10 (0.8H, q J=8 Hz), 7.24 (0.6H, m), 7.39 (0.6H,s), 7.45 (0.4H, m), 7.54 (1H, s), 8.49 (1H, m).

MS (ESI⁺): m/z 298 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Prepatration 78.

Preparation 257

ethyl 5-(2-chloroisonicotinoyl)-6-oxoheptanoate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.60-1.73 (2H, m), 1.98-2.10 (2H,m), 2.20 (3H, s), 2.35 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.37 (1H,t, J=7 Hz), 7.67 (1H, d, J=5 Hz), 7.77 (1H, s), 8.59 (1H, d, J=5 Hz).

MS (ESI⁺): m/z 312.

Preparation 258

ethyl 4-(2-chloroisonicotinoyl)-5-oxohexanoate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 2.21 (3H, s), 2.22-2.35 (2H, m),2.36-2.47 (2H, m), 4.12 (2H, q, J=7 Hz), 4.57 (1H, t, J=7 Hz), 7.76 (1H,dd, J=2 Hz, 5 Hz), 7.83 (1H, d, J=2 Hz), 8.61 (1H, d, J=5 Hz).

MS (ESI⁺): m/z 298.

Preparation 259

ethyl 6-(2-chloroisonicotinoyl)-7-oxo-8-phenyloctanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.20-1.38 (2H, m), 1.60-1.72 (2H,m), 1.95-2.06 (2H, m), 2.28 (2H, t, J=7 Hz), 3.71 (1H, d, J=17 Hz), 3.80(1H, d, J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.41 (1H, t, J=7 Hz), 7.10 (2H,m), 7.20-7.33 (4H, m), 7.39 (1H, s), 8.42 (1H, d, J=5 Hz).

Preparation 260

methyl ({3-[(5-methyl-3-pyridinyl)carbonyl]-4-oxopentyl}oxy)acetate

¹H NMR (CDCl₃) δ 2.23 (3H, s), 2.23-2.40 (2H, m), 2.44 (3H, s), 3.58(2H, m), 3.71 (3H, s), 4.02 (2H, s), 4.89 (1H, t, J=7 Hz), 8.12 (1H, s),8.64 (1H, s), 9.07 (1H, s).

MS (ESI⁺): m/z 294.

Preparation 261

methyl(4-oxo-4-phenylbutoxy)acetate

¹H NMR (CDCl₃) δ 2.04-2.16 (2H, m), 3.15 (2H, t, J=7 Hz), 3.64 (2H, t,J=7 Hz), 3.73 (3H, s), 4.09 (2H, s), 7.46 (2H, t, J=8 Hz), 7.56 (1H, t,J=8 Hz), 7.99 (2H, d, J=8 Hz).

MS (ESI⁺): m/z 237.

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 78.

Preparation 262

ethyl 3-[(5-bromo-3-pyridinyl)carbonyl]-4-oxopentanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 2.22 (3H, s), 2.97-3.17 (2H, m),4.12 (2H, q, J=7 Hz), 4.91 (1H, m), 8.41 (1H, m), 8.88 (1H, m), 9.12(1H, m).

MS (ESI⁺): m/z 328 330.

Preparation 263

ethyl 6-(acetyloxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.98 (3H, s), 2.23-2.34 (2H, m),2.40-2.50 (2H, m), 2.45 (3H, s), 4.12 (2H, q, J=7 Hz), 4.69 (2H, m),4.82 (1H, t, J=7 Hz), 8.14 (1H, s), 8.67 (1H, s), 9.07 (1H, s).

MS (ESI⁺): m/z 336.

Preparation 264

ethyl 7-(acetyloxy)-5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxoheptanoate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.60-1.80 (2H, m), 2.02 (3H, s),1.97-2.13 (2H, m), 2.35 (2H, t, J=7 Hz), 2.45 (3H, s), 4.12 (2H, q, J=7Hz), 4.56 (1H, t, J=7 Hz), 4.69 (1H, d, J=17 Hz), 4.78 (1H, d, J=17 Hz),8.06 (1H, s), 8.66 (1H, s), 9.00 (1H, s).

MS (ESI⁺): m/z 350.

Preparation 265

ethyl 8-(acetyloxy)-6-(3-cyanobenzoyl)-7-oxooctanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.35-1.50 (2H, m), 1.60-1.78 (2H,m), 2.04 (3H, s), 2.00-2.12 (2H, m), 2.29 (2H, t, J=7 Hz), 4.12 (2H, q,J=7 Hz), 4.49 (1H, t, J=7 Hz), 4.68 (1H, d, J=17 Hz), 4.75 (1H, d, J=17Hz), 7.66 (1H, t, J=8 Hz), 7.88 (1H, d, J=8 Hz), 8.16 (1H, d, J=8 Hz),8.26 (1H, s).

MS (ESI⁻): m/z 372.

Preparation 266

ethyl 7-(acetyloxy)-5-[(5-bromo-3-pyridinyl)carbonyl]-6-oxoheptanoate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.60-1.82 (2H, m), 2.04 (3H, s),2.03-2.15 (2H, m), 2.35 (2H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.51 (1H,t, J=7 Hz), 4.70 (1H, d, J=17 Hz), 4.75 (1H, d, J=17 Hz), 8.39 (1H, m),8.88 (1H, s), 9.07 (1H, s).

MS (ESI⁻): m/z 414 416, MS (ESI⁺): m/z 414 416.

Preparation 267

ethyl 6-(acetyloxy)-4-[(5-bromo-3-pyridinyl)carbonyl]-5-oxohexanoate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 2.00 (3H, s), 2.22-2.36 (2H, m),2.43-2.53 (2H, m), 4.13 (2H, q, J=7 Hz), 4.70 (2H, m), 4.80 (1H, t, J=7Hz), 8.48 (1H, s), 8.90 (1H, s), 9.19 (1H, s).

MS (ESI⁺): m/z 400 402.

Preparation 268

ethyl6-(cyclohexylmethoxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

¹H NMR (CDCl₃) δ 0.60-0.82 (2H, m), 0.93-1.10 (3H, m), 1.12-1.65 (6H,m), 1.25 (3H, t, J=7 Hz), 2.07-2.17 (1H, m), 2.22-2.35 (1H, m), 2.42(2H, m), 2.44 (3H, s), 3.05-3.23 (2H, m), 3.96 (2H, s), 4.12 (2H, q, J=7Hz), 4.92 (1H, m), 8.16 (1H, s), 8.66 (1H, s), 9.08 (1H, s).

MS (ESI⁺): m/z 390.

Preparation 269

ethyl4-[(5-bromo-3-pyridinyl)carbonyl]-6-(cyclohexylmethoxy)-5-oxohexanoate

¹H NMR (CDCl₃) δ 0.63-0.84 (2H, m), 0.93-1.88 (3H, m), 1.25 (3H, t, J=7Hz), 1.35-1.90 (6H, m), 2.02-2.14 (1H, m), 2.20-2.36 (1H, m), 2.44 (2H,t, J=7 Hz), 3.04-3.20 (2H, m), 3.95 (2H, s), 4.13 (2H, q, J=7 Hz),4.854.93 (1H, m), 8.50 (1H, m), 8.88 (1H, d, J=2 Hz), 9.20 (1H, d, J=2Hz).

MS (ESI⁺): m/z 454 456.

Preparation 270

ethyl5-[(5-bromo-3-pyridinyl)carbonyl]-7-(cyclohexylmethoxy)-6-oxoheptanoate

¹H NMR (300 MHz, CDCl₃) δ 0.75-0.86 (2H, m), 0.95-1.15 (3H, m), 1.24(3H, t, J=57 Hz), 1.40-1.90 (10H, m), 2.36 (2H, t, J=7 Hz), 3.12 (2H, q,J=7 Hz), 3.97 (2H, s), 4.12 (2H, q, J=7 Hz), 4.71 (1H, t, J=7 Hz), 8.41(1H, s), 8.88 (1H, s), 9.12 (1H, s).

MS (ESI⁺): m/z 468 470.

Preparation 271

ethyl7-(cyclopropylmethoxy)-5-[(5-methyl-3-pyridinyl)carbonyl]-6-oxoheptanoate

¹H NMR (CDCl₃) δ −0.08-0.00 (1H, m), 0.00-0.15 (1H, m), 0.28-0.49 (2H,m), 0.72-0.87 (1H, m), 1.23 (3H, t, J=7 Hz), 1.58-2.13 (4H, m), 2.32(2H, t, J=7 Hz), 2.44 (3H, s), 3.10-3.26 (2H, m), 4.02 (2H, m), 4.12(2H, q, J=7 Hz), 4.77 (1H, t, J=7 Hz), 8.07 (1H, s), 8.63 (1H, s), 9.03(1H, s).

MS (ESI⁺): m/z 362.

Preparation 272

ethyl6-(cyclopropylmethoxy)-4-[(5-methyl-3-pyridinyl)carbonyl]-5-oxohexanoate

¹H NMR (CDCl₃) δ −0.08-0.00 (1H, m), 0.00-0.13 (1H, m), 0.23-0.47 (2H,m), 0.68-0.84 (1H, m), 1.24 (3H, t, J=7 Hz), 2.03-2.17 (1H, m),2.22-2.36 (1H, m), 2.40 (2H, m), 2.44 (3H, s), 3.12 (2H, m), 3.98 (1H,d, J=17 Hz), 4.06 (1H, d, J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.93 (1H, m),8.12 (1H, s), 8.65 (1H, s), 9.08 (1H, s).

MS (ESI⁺): m/z 348.

Preparation 273

ethyl4-[(5-bromo-3-pyridinyl)carbonyl]-6-(2-methoxyethoxy)-5-oxohexanoate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.90-2.37 (2H, m), 2.43 (2H, t,J=7 Hz), 3.18 (3H, s), 3.16-3.73 (4H, m), 4.06 (2H, q, J=7 Hz),4.10-4.24 (2H, m), 4.86-4.93 (1H, m), 8.51 (1H, m), 8.87 (1H, d, J=2Hz), 9.20 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 414 416, MS (ESI⁺): m/z 416 418.

Preparation 274

1-(5-bromo-3-pyridinyl)-1,3-butanedione

¹H NMR (CDCl₃) δ 2.25 (3H, s), 6.18 (1H, s), 8.31 (1H, s), 8.78 (1H, s),8.96 (1H, s).

MS (ESI⁺): m/z 242 244.

Preparation 275

ethyl 7-(acetyloxy)-5-[(5-chloro-3-pyridinyl)carbonyl]-6-oxoheptanoate

¹H NMR (300 MHz, CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.60-1.70 (4H, m), 2.04(3H, s), 2.35 (2H, t, J=6 Hz), 4.12 (2H, q, J=7 Hz), 4.52 (1H, t, J=7Hz), 4.69 (1H, d, J=18 Hz), 4.78 (1H, d, J=18 Hz), 8.24 (1H, s), 8.78(1H, s), 9.05 (1H, s).

Preparation 276

ethyl6-[(5-chloro-3-pyridinyl)carbonyl]-8-(cyclopropylmethoxy)-7-oxooctanoate

¹H NMR (300 MHz, CDCl₃) δ−0.09-0.11 (2H, m), 0.25-0.35 (1H, m),0.37-0.46 (1H, m), 0.70-0.79 (1H, m), 1.24 (3H, t, J=7 Hz), 1.29-1.41(2H, m), 1.64 (2H, t, J=7 Hz), 1.72-1.84 (1H, m), 1.96-2.08 (1H, m),2.28 (2H, t, J=7 Hz), 3.12 (1H, dd, J=10, 7 Hz), 3.21 (1H, dd, J=10, 7Hz), 3.97 (1H, d, J=12 Hz), 4.05 (1H, d, J=12 Hz), 4.11 (2H, q, J=7 Hz),4.70 (1H, t, J=7 Hz), 8.26 (1H, dd, J=2, 2 Hz), 8.77 (1H, dd, J=2 Hz),9.09 (1H, dd, J=2 Hz).

Preparation 277

ethyl5-[(5-chloro-3-pyridinyl)carbonyl]-7-(cyclopropylmethoxy)-6-oxoheptanoate

¹H NMR (300 MHz, CDCl₃) δ −0.07-0.09 (2H, m), 0.24-0.46 (2H, m),0.68-0.79 (1H, m), 1.23 (3H, t, J=7 Hz), 1.47-1.84 (3H, m), 1.98-2.10(1H, m), 2.33 (2H, t, J=7 Hz), 3.12 (1H, dd, J=10, 7 Hz), 3.21 (1H, dd,J=10, 7 Hz), 3.97 (1H, d, J=17 Hz), 4.06 (1H, d, J=17 Hz), 4.10 (2H, q,J=7 Hz), 4.73 (1H, t, J=6 Hz), 8.27 (1H, dd, J=2, 2 Hz), 8.77 (1H, d,J=2 Hz), 9.10 (1H, d, J=2 Hz).

Preparation 278

ethyl 6-[(5-bromo-3-pyridinyl)carbonyl]-8-isobutoxy-7-oxooctanoate

¹H NMR (300 MHz, CDCl₃) δ 0.72 (3H, d, J=7 Hz), 0.77 (3H, d, J=7 Hz),1.24 (3H, t, J=7 Hz), 1.30-1.42 (2H, m), 1.54-1.70 (3H, m), 1.75-1.87(1H, m), 1.95-2.08 (1H, m), 2.28 (2H, t, J=8 Hz), 3.10 (1H, dd, J=9, 7Hz), 3.14 (1H, dd, J=9, 7 Hz), 3.98 (2H, s), 4.11 (2H, q, J=7 Hz), 4.70(1H, t, J=6 Hz), 8.39 (1H, dd, J=2 Hz), 8.87 (1H, d, J=2 Hz), 9.08 (1H,d, J=2 Hz).

Preparation 279

ethyl 4-[(5-chloro-3-pyridinyl)carbonyl]-6-isobutoxy-5-oxohexanoate

¹H NMR (300 MHz, CDCl₃) δ 0.68 (3H, d, J=7 Hz), 0.72 (3H, d, J=7 Hz),1.25 (3H, t, J=7 Hz), 1.52 (1H, qt, J=7, 7 Hz), 2.02-2.13 (1H, m),2.20-2.32 (1H, m), 2.44 (2H, t, J=7 Hz), 3.07 (1H, dd, J=9, 7 Hz), 3.12(1H, dd, J=9, 7 Hz), 3.98 (2H, s), 4.14 (2H, q, J=7 Hz), 4.90 (1H, d,J=9 Hz), 4.92 (1H, d, J=9 Hz), 8.34 (1H, dd, J=2 Hz), 8.78 (1H, d, J=2Hz), 9.15 (1H, d, J=2 Hz).

Preparation 280

ethyl 6-(acetyloxy)-4-(3-chlorobenzoyl)-5-oxohexanoate

¹H NMR (300 MHz, CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.95 (3H, s), 2.20-2.29(2H, m), 2.41-2.47 (2H, m), 4.15 (2H, q, J=7 Hz), 4.64 (1H, d, J=17 Hz),4.71 (1H, d, J=17 Hz), 4.78 (1H, t, J=6 Hz), 7.48 (1H, dd, J=8, 8 Hz),7.60 (1H, d, J=8 Hz), 7.96 (1H, d, J=8 Hz), 8.04 (1H, s).

Preparation 281

ethyl 5-[(5-bromo-3-pyridinyl)carbonyl]-7-isobutoxy-6-oxoheptanoate

¹H NMR (300 MHz, CDCl₃) δ 0.72 (3H, d, J=7 Hz), 0.77 (3H, d, J=7 Hz),1.23 (3H, t, J=7 Hz), 1.61-1.73 (3H, m), 1.77-1.88 (1H, m), 1.98-2.10(1H, m), 2.33 (2H, t, J=7 Hz), 3.10 (1H, dd, J=9, 7 Hz), 3.15 (1H, dd,J=9, 7 Hz), 3.99 (2H, s), 4.11 (2H, q, J=7 Hz), 4.73 (1H, t, J=7 Hz),8.40 (1H, dd, J=2, 2 Hz), 8.87 (1H, d, J=2 Hz), 9.10 (1H, d, J=2 Hz).

Preparation 282

1,3-bis(5-bromo-3-pyridinyl)-1,3-propanedione

¹H NMR (DMSO-d₆) δ 7.60 (1H, s), 8.78 (2H, s), 8.88 (2H, s), 9.30 (2H,s).

Preparation 283

ethyl 7-(acetyloxy)-5-(3-chlorobenzoyl)-6-oxoheptanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=8 Hz), 1.57-1.75 (2H, m), 1.90-2.12 (5H,m), 2.34 (2H, t, J=8 Hz), 4.11 (2H, q, J=8 Hz), 4.52 (1H, t, J=8 Hz),4.71 (2H, q, J=8 Hz), 4.65 (1H, d, J=16 Hz), 4.75 (1H, d, J=16 Hz), 7.43(1H, t, J=8 Hz), 7.60 (1H, br d, J=8 Hz), 7.84 (1H, br d, J=8 Hz), 7.96(1H, br s).

Preparation 284

ethyl 8-methoxy-6-[(5-methoxy-3-pyridinyl)carbonyl]-7-oxooctanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=8 Hz), 1.27-1.43 (2H, m), 1.55-1.70 (2H,m), 1.84 (1H, m), 2.00 (1H, m), 2.27 (2H, d, J=8 Hz), 3.26 (3H, s), 3.92(3H, s), 3.98 (2H, d, J=5 Hz), 4.10 (2H, q, J=8 Hz), 4.67 (1H, t, J=8Hz), 7.71 (1H, m), 8.50 (1H, d, J=3 Hz), 8.78 (1H, br s).

MS (ESI⁺): m/z 352 (M+H).

Preparation 285

ethyl 6-[(5-methoxy-3-pyridinyl)carbonyl]-7-oxooctanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=8 Hz), 1.27-1.41 (2H, m), 1.60-1.73 (2H,m), 1.90-2.14 (2H, m), 2.18 (3H, s), 2.24-2.84 (2H, m), 3.26 (3H, s),3.92 (3H, s), 4.10 (2H, q, J=8 Hz), 4.40 (1H, t, J=8 Hz), 7.71 (1H, m),8.51 (1H, d, J=3 Hz), 8.78 (1H, br s).

Preparation 286

ethyl 6-methoxy-4-[(5-methoxy-3-pyridinyl)carbonyl]-5-oxohexanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=8 Hz), 2.10 (1H, m), 2.25 (1H, m),2.38-2.47 (2H, m), 3.24 (3H, s), 3.94 (3H, s), 3.95 (1H, d, J=16 Hz),4.00 (1H, d, J=16 Hz), 4.12 (2H, q, J=8 Hz), 4.38 (1H, m), 7.83 (1H, m),8.52 (1H, d, J=3 Hz), 8.87 (1H, d, J=1 Hz).

MS (ESI⁺): m/z 346 (M++Na).

Preparation 287

ethyl 7-methoxy-5-[(5-methoxy-3-pyridinyl)carbonyl]-6-oxoheptanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=8 Hz), 1.54-1.74 (2H, m), 1.84 (1H, m),2.02 (1H, m), 2.32 (2H, d, J=8 Hz), 3.26 (3H, s), 3.92 (3H, s), 3.99(2H, d, J=5 Hz), 4.10 (2H, q, J=8 Hz), 4.70 (1H, t, J=8 Hz), 7.71 (1H,m), 8.51 (1H, d, J=3 Hz), 8.79 (1H, br s).

MS (ESI⁺): m/z 338 (M+H).

Preparation 288

ethyl 8-methoxy-7-oxo-6-(5-pyrimidinylcarbonyl)octanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=8 Hz), 1.25-1.45 (2H, m), 1.55-1.70 (2H,m), δ 1.81 (1H, m), 2.03 (1H, m), 2.28 (2H, t, J=8 Hz), 3.24 (3H, s),3.92 (1H, d, J=18 Hz), 4.01 (1H, d, J=18 Hz), 4.10 (2H, q, J=8 Hz), 9.26(2H, s), 9.40 (1H, s).

MS (ESI⁺): m/z 323 (M+H).

Preparation 289

ethyl 5-[(5-chloro-3-pyridinyl)carbonyl]-7-methoxy-6-oxoheptanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=8 Hz), 1.52-1.74 (2H, m), 1.83 (1H, m),2.02 (1H, m), 2.34-2.40 (2H, m), 3.25 (3H, s), 3.92 (1H, d, J=16 Hz),4.01 (1H, d, J=16 Hz), 4.11 (2H, q, J=8 Hz), 4.68 (1H, t, J=8 Hz), 8.23(1H, br s), 8.78 (1H, br s), 9.05 (1H, br s).

MS (ESI⁺): m/z 342 (M+H).

Preparation 290

ethyl 4-[(5-chloro-3-pyridinyl)carbonyl]-6-methoxy-5-oxohexanoate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=8 Hz), 2.09 (1H, m), 2.25 (1H, m),2.38-2.49 (2H, m), 3.22 (3H, s), 3.91 (1H, d, J=18 Hz), 4.00 (1H, d,J=18 Hz), 4.14 (2H, q, J=8 Hz), 4.85 (1H, m), 8.33 (1H, br s), 8.78 (1H,br s), 9.14 (1H, br s).

MS (ESI⁺): m/z 328 (M+H).

Preparation 291

ethyl 6-[(5-chloro-3-pyridinyl)carbonyl]-8-methoxy-7-oxooctanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=8 Hz), 1.27-1.43 (2H, m), 1.50-1.71 (2H,m), 1.82 (1H, m), 2.00 (1H, m), 2.27 (2H, d, J=8 Hz), 3.25 (3H, s), 3.92(1H, d, J=16 Hz), 4.02 (1H, d, J=16 Hz), 4.10 (2H, q, J=8 Hz), 4.63 (1H,t, J=8 Hz), 8.23 (1H, br s), 8.78 (1H, br s), 9.03 (1H, br s).

MS (ESI⁺): m/z 356 (M+H).

Preparation 292

2-[2-({3-[(5-methyl-3-pyridinyl)carbonyl]-4-oxopentyl}oxy)ethoxy]ethylacetate trifluoroacetate

¹H-NMR (CDCl₃) δ 2.06 (3H, s), 2.28 (3H, s), 2.33 (2H, m), 2.65 (3H, s),3.47-3.67 (8H, m), 4.17 (2H, m), 4.71 (1H, t, J=7 Hz), 8.66 (1H, m),8.88 (11H, m), 9.31 (11H, m).

Preparation 293

ethyl 5-[(5-bromo-3-pyridinyl)carbonyl]-7-methoxy-6-oxoheptanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.56-1.73 (2H, m), 1.77-1.92 (1H,m), 1.96-2.10 (1H, m), 2.32 (2H, t, J=7 Hz), 3.25 (3H, s), 3.92 (1H, d,J=17 Hz), 4.02 (1H, d, J=17 Hz), 4.12 (2H, q, J=7 Hz), 4.67 (1H, t, J=7Hz), 8.39 (1H, m), 8.87 (1H, d, J=2 Hz), 9.09 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 386 388.

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 129 and 130.

Preparation 294

tert-butyl 3-oxo-4-phenylbutanoate

¹H NMR (CDCl₃) δ 1.46 (9H, s), 3.37 (2H, s), 3.82 (2H, s), 7.21 (2H, d,J=8 Hz), 7.25-7.37 (3H, m).

Preparation 295

tert-butyl 3-oxo-3-phenylpropanoate

¹H NMR (CDCl₃) δ 1.43 (9H, s), 3.81 (2H, s), 7.40-7.52 (2H, m),7.56-7.63 (1H, m), 7.94 (2H, d, J=8 Hz).

Preparation 296

tert-butyl 4-(cyclohexylmethoxy)-3-oxobutanoate

¹H NMR (CDCl₃) δ 0.89-1.07 (2H, m), 1.13-1.40 (3H, m), 1.47 (9H, s),1.60-1.83 (6H, m), 3.28 (2H, d, J=7 Hz), 3.45 (2H, s), 4.06 (2H, s).

Preparation 297

tert-butyl 4-(cyclopropylmethoxy)-3-oxobutanoate

¹H NMR (CDCl₃) δ 0.20-0.28 (2H, m), 0.55-0.64 (2H, m), 1.03-1.17 (1H,m), 1.47 (9H, s), 3.36 (2H, d, J=7 Hz), 3.45 (2H, s), 4.15 (2H, s).

Preparation 298

tert-butyl 4-(2-methoxyethoxy)-3-oxobutanoate

¹H NMR (CDCl₃) δ 1.47 (9H, s), 3.38 (3H, s), 3.44 (2H, s), 3.57 (2H, m),3.70 (2H, m), 4.20 (2H, s).

Preparation 299

tert-butyl 4-isobutoxy-3-oxobutanoate

¹H NMR (300 MHz, CDCl₃) δ 0.93 (6H, d, J=7 Hz), 1.45 (9H, s), 1.91 (1H,qt, J=7, 7 Hz), 3.26 (2H, d, J=7 Hz), 3.45 (2H, s), 4.07 (2H, s).

Preparation 300

tert-butyl 3-(3-methyl-2-thienyl)-3-oxopropanoate

¹H-NMR (CDCl₃) δ 1.47 (9H, s), 2.57 (3H, s), 3.79 (2H, s), 6.96 (1H, d,J=5 Hz), 7.44 (1H, d, J=5 Hz).

Preparation 301

tert-butyl 3-(5-methyl-3-isoxazolyl)-3-oxopropanoate

¹H-NMR (CDCl₃) δ 1.475-1.57 (9H, m), 2.49 (3H, m), 3.95 (2H, s), 6.40(1H, s).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 132.

Preparation 302

ethyl (2E)-5-(3-cyanobenzoyl)-6-oxo-2-heptenoate

¹H-NMR (CDCl₃) δ 1.28 (3H, t, J=7 Hz), 2.20 (3H, s), 2.88 (2H, m), 4.16(2H, q, J=7 Hz), 4.54 (1H, t, J=7 Hz), 5.88 (1H, d, J=16 Hz), 6.82 (1H,dt, J=7 and 16 Hz), 7.65 (1H, t, J=8 Hz), 7.89 (1H, d, J=8 Hz), 8.20(1H, d, J=8 Hz), 8.27 (1H, s).

MS (ESI⁺): m/z 300.14 (M+H)

Preparation 303

1-tert-butyl 7-ethyl 2-[(3-methyl-2-thienyl)carbonyl]heptanedioate

¹H-NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.35-1.51 (11H, m), 1.65 (2H, m),1.96 (2H, m), 2.30 (2H, t, J=7 Hz), 2.58 (3H, s), 3.94 (1H, t, J=7 Hz),4.12 (2H, q, J=7 Hz), 6.97 (1H, d, J=5 Hz), 7.44 (1H, d, J=5 Hz).

Preparation 304

1-tert-butyl 7-ethyl 2-[(5-methyl-3-isoxazolyl)carbonyl]heptanedioate

¹H-NMR (CDCl₃) δ 11.24 (3H, t, J=7 Hz), 1.39 (9H, s), 1.67 (2H, m), 1.98(2H, m), 2.49 (3H, s), 4.10 (2H, q, J=7 Hz), 4.26 (1H, t, J=7 Hz), 6.37(1H, s).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 152.

Preparation 305

methyl 7-oxo-7-(2-thienyl)heptanoate

¹H-NMR (CDCl₃) δ 1.41 (2H, m), 1.63-1.82 (4H, m), 2.33 (2H, t, J=7 Hz),2.91 (2H, t, J=7 Hz), 3.67 (3H, s), 1.73 (1H, m), 7.62 (1H, m), 7.70(1H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 153.

Preparation 306

5-methoxynicotinoyl chloride hydrochloride

Preparation 307

5-pyrimidinecarbonyl chloride hydrochloride

Preparation 308

5-chloronicotinoyl chloride hydrochloride

Preparation 309

methyl 2-bromo-4-(chlorocarbonyl)benzoate

The following compound(s) was (were) obtained in a similar manner tothat of Praparation 159.

Preparation 310

1-tert-butyl 7-ethyl 2-(phenylacetyl)heptanedioate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.18-1.50 (2H, m), 1.46 (9H, s),1.50-1.75 (2H, m), 1.75-1.88 (2H, m), 2.24 (2H, t, J=7 Hz), 3.47 (1H, t,J=7 Hz), 3.81 (2H, s), 4.10 (2H, q, J=7 Hz), 7.20 (2H, d, J=8 Hz),7.25-7.37 (3H, m).

Preparation 311

tert-butyl 2-[2-(2-methoxy-2-oxoethoxy)ethyl]-3-oxobutanoate

¹H NMR (CDCl₃) δ 1.46 (9H, s), 2.04-2.23 (2H, m), 2.29 (3H, s), 3.54(2H, t, J=7 Hz), 3.69 (1H, t, J=7 Hz), 3.74 (3H, s), 4.04 (2H, s).

Preparation 312

tert-butyl 2-benzoyl-4-(2-methoxy-2-oxoethoxy)butanoate

¹H NMR (CDCl₃) δ 1.34 (9H, s), 2.26-2.40 (2H, m), 3.55-3.67 (2H, m),3.70 (3H, s), 4.04 (2H, s), 4.57 (1H, t, J=7 Hz), 7.47 (2H, t, J=8 Hz),7.56 (1H, m), 8.01 (2H, d, J=8 Hz).

Preparation 313

1-tert-butyl 6-ethyl 2-[(acetyloxy)acetyl]hexanedioate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.48 (9H, s), 1.60-1.73 (2H, m),1.82-1.95 (2H, m), 2.17 (3H, s), 2.32 (2H, t, J=7 Hz), 3.43 (1H, t, J=7Hz), 4.12 (2H, q, J=7 Hz), 4.72 (1H, d, J=17 Hz), 4.83 (1H, d, J=17 Hz).

Preparation 314

1-tert-butyl 5-ethyl 2-[(cyclohexylmethoxy)acetyl]pentanedioate

¹H NMR (CDCl₃) δ 0.85-1.06 (2H, m), 1.13-1.34 (3H, m), 1.26 (3H, t, J=7Hz), 1.45 (9H, s), 1.60-1.85 (6H, m), 2.08-2.23 (2H, m), 2.36 (2H, t,J=7 Hz), 3.27 (2H, d, J=7 Hz), 3.67 (1H, t, J=7 Hz), 4.10 (2H, s), 4.12(2H, q, J=7 Hz).

Preparation 315

1-tert-butyl 6-ethyl 2-[(cyclohexylmethoxy)acetyl]hexanedioate

¹H NMR (CDCl₃) δ0.88-1.06 (2H, m), 1.12-1.34 (3H, m), 1.25 (3H, t, J=7Hz), 1.45 (9H, s), 1.54-1.94 (10H, m), 2.32 (2H, t, J=7 Hz), 3.27 (2H,d, J=7 Hz), 3.56 (1H, t, J=7 Hz), 4.09 (2H, s), 4.11 (2H, q, J=7 Hz).

MS (ESI⁺): m/z 385.

Preparation 316

1-tert-butyl 6-ethyl 2-[(cyclopropylmethoxy)acetyl]hexanedioate

¹H NMR (CDCl₃) δ 0.22-0.33 (2H, m), 0.54-0.64 (2H, m), 1.04-1.18 (1H,m), 1.25 (3H, t, J=7 Hz), 1.45 (9H, s), 1.60-1.73 (2H, m), 1.83-1.95(2H, m), 2.33 (2H, t, J=7 Hz), 3.33 (2H, d, J=7 Hz), 3.53 (1H, t, J=7Hz), 4.12 (2H, q, J=7 Hz), 4.18 (2H, m).

MS (ESI⁺): m/z 343.

Preparation 317

1-tert-butyl 5-ethyl 2-[(cyclopropylmethoxy)acetyl]pentanedioate

¹H NMR (CDCl₃) δ 0.20-0.35 (2H, m), 0.56-0.64 (2H, m), 1.04-1.16 (1H,m), 1.26 (3H, t, J=7 Hz), 1.45 (9H, s), 2.12-2.24 (2H, m), 2.38 (2H, t,J=7 Hz), 3.36 (2H, m), 3.65 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.19(2H, s).

Preparation 318

1-tert-butyl 5-ethyl 2-[(2-methoxyethoxy)acetyl]pentanedioate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.46 (9H, s), 2.10-2.23 (2H, m),2.38 (2H, t, J=7 Hz), 3.37 (3H, s), 3.60 (2H, m), 3.62 (1H, t, J=7 Hz),3.70 (2H, m), 4.12 (2H, q, J=7 Hz), 4.23 (1H, d, J=17 Hz), 4.30 (1H, d,J=17 Hz).

MS (ESI⁺): m/z 333.

Preparation 319

1-tert-butyl 5-ethyl 2-(isobutoxyacetyl)pentanedioate

¹H NMR (300 MHz, CDCl₃) δ 0.93 (6H, d, J=7 Hz), 1.26 (3H, t, J=7 Hz),1.45 (9H, s), 1.91 (1H, qt, J=7, 7 Hz), 2.13 (2H, m), 2.37 (2H, t, J=7Hz), 3.25 (2H, d, J=7 Hz), 3.67 (1H, t, J=7 Hz), 4.12 (2H, s), 4.13 (2H,q, J=7 Hz).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 164.

Preparation 320

methyl 2-bromo-4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate

¹H-NMR (CDCl₃) δ 1.32 (3H, t, J=7 Hz), 2.72 (2H, q, J=7 Hz), 3.97 (3H,s), 6.10 (1H, m), 6.77 (1H, m), 7.81 (1H, d, J=8 Hz), 7.85 (1H, d, J=8Hz), 8.11 (1H, s), 9.32 (1H, s, br).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 165.

Preparation 321

tert-butyl 2-(2-{2-[2-(acetyloxy)ethoxy]ethoxy}ethyl)-3-oxobutanoate

¹H-NMR (CDCl₃) δ 1.46 (9H, s), 2.00-2.17 (5H, m), 2.25 (3H, s),3.45-3.70 (10H, m), 4.22 (2H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 178.

Preparation 322

Isobutoxyacetic Acid

¹H NMR (300 MHz, CDCl₃) δ 0.94 (6H, d, J=7 Hz), 1.93 (1H, qt, J=7, 7Hz), 3.34 (2H, d, J=7 Hz), 4.12 (2H, s).

Preparation 323

To a suspension of 60% NaH (2.66 g) in DMF (20 mL) was added methylhydroxyacetate (5.00 g) under ice-water cooling, and the mixture wasstirred at 0° C. for 0.5 hour. To this was added2-(2-bromoethoxy)tetrahydro-2H-pyran (12.8 g) under ice-water cooling,and the mixture was stirred at ambient temperature for 2 hours. Themixture was partitioned between AcOEt and water. The organic layer wasseparated, washed with water and brine, dried over MgSO₄, and evaporatedin vacuo. The residue was purified by silica gel column chromatographyeluting with a mixture of hexane and AcOEt (10:1-3:1) to givemethyl[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate pale yellow oil(445 g).

methyl[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate

¹H NMR (CDCl₃) δ 1.48-1.95 (6H, m), 3.46-3.57 (2H, m), 3.64-3.75 (2H,m), 3.76 (3H, s), 3.82-3.97 (2H, m), 4.20 (2H, s), 4.66 (1H, m).

Preparation 324

A mixture of methyl[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]acetate (1.07g) and pyridinium p-toluenesulfonate (24.6 mg) in MeOH (10 mL) washeated under reflux for 2 hours. After evaporation of solvent, theresidue was purified by silica gel column chromatography eluting with amixture of hexane and AcOEt (10:1-1:3) to give methyl(2-hydroxyethoxy)acetate as colorless oil (555 mg).

methyl(2-hydroxyethoxy)acetate

¹H NMR (CDCl₃) δ 3.69 (2H, m), 3.76 (2H, m), 3.78 (3H, s), 4.16 (2H, s).

Preparation 325

To solution of methyl(2-hydroxyethoxy)acetate (540 mg), imidazole (411mg) and triphenylphosphine (1.37 g) in ether (2 mL) and CH₃CN (1 mL) wasadded iodine (1.43 g) under ice-water cooling and the mixture wasstirred at 0° C. for 2 hours. After insolubles were filterred off, thefiltrates were diluted with AcOEt, washed with aq Na₂SO₃ solution andbrine, dried over MgSO₄, and evaporated in vacuo. The residue waspurified by silica gel column chromatography eluting with a mixture ofhexane and AcOEt (20:1-5:1) to give methyl(2-iodoethoxy)acetate ascolorless oil (898 mg).

methyl(2-iodoethoxy)acetate

¹H NMR (CDCl₃) δ 3.30 (2H, t, J=7 Hz), 3.77 (3H, s), 3.84 (2H, t, J=7Hz), 4.17 (2H, s).

Preparation 326

To a suspension of 60% NaH (1.02 g) in THF (50 mL) was added tert-butyl4-(acetyloxy)-3-oxobutanoate (5.00 g) under ice-water cooling and themixture was stirred at 0° C. for 0.5 hour. To this added ethyl3-iodopropanoate (5.54 g) and the mixture was stirred at 50° C. for 8hours. The mixture was partitioned between AcOEt and water. The organiclayer was separated, washed with brine, dried over MgSO₄, and evaporatedin vacuo. The residue was purified by silica gel column chromatographyeluting with a mixture of hexane and AcOEt (20:1-3:1) to give1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]pentanedioate as yellow oil(4.27 g).

1-tert-butyl 5-ethyl 2-[(acetyloxy)acetyl]pentanedioate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.46 (9H, s), 2.14-2.24 (2H, m),2.17 (3H, s), 2.36 (2H, t, J=7 Hz), 3.60 (1H, t, J=7 Hz), 4.12 (2H, q,J=7 Hz), 4.73 (1H, d, J=18 Hz), 4.83 (1H, d, J=18 Hz).

Preparation 327

To a solution of benzyl 4-thiomorpholinecarboxylate (4.8 g) in methanol(30 mL) and H₂O (20 mL) was added oxone (16.2 g) under ice water coolingand the mixture was stirred at ambient temperature for 2 hours. Thesolution was evaporated in vacuo and partitioned between EtOAc andwater. The aqueous layer was extracted with EtOAc. The combined organiclayer was washed with water and brine, dried over MgSO₄ and evaporatedin vacuo. The residue was purified by silica gel column chromatographyeluting with a mixture of hexane and EtOAc to give benzyl4-thiomorpholinecarboxylate 1,1-dioxide as a colorless solid (3.8 g).

benzyl 4-thiomorpholinecarboxylate 1,1-dioxide

¹H NMR (300 MHz, CDCl₃) δ 3.02 (4H, br s), 4.01 (4H, t, J=5 Hz), 5.16(2H, s), 7.33-7.40 (5H, m).

Preparation 328

To a solution of thiomorpholine (2 g) in 1N NaOH (11.6 mL) was addedbenzyl chloridocarbonate (1.66 mL) under ice water cooling and themixture was stirred at ambient temperature for 2 hours. The solution wasneutrolized with 1N HCl and extracted with EtOAc twice. The combinedorganic layer was washed with water and brine, dried over MgSO₄ andevaporated in vacuo. The residue was purified by silica gel columnchromatography to give benzyl 4-thiomorpholinecarboxylate as a colorlesssolid (4.8 g).

benzyl 4-thiomorpholinecarboxylate

¹H NMR (300 MHz, CDCl₃) δ 2.59 (4H, br s), 3.77 (4H, t, J=5 Hz), 5.14(2H, s), 7.30-7.41 (5H, m).

Preparation 329

To a solution of benzyl 4-thiomorpholinecarboxylate 1,1-dioxide (3.8 g)in methanol (32 mL) and 1,4-dioxane (8 mL) was added Palladium, 10 wt. %on activated carbon (380 mg) at ambient temperature. The mixture wasstirred at ambient temperature for 4 hours under H₂ (3.4 atom). Themixture was filtered and evaporated in vacuo to give thiomorpholine1,1-dioxide as a colorless solid (2.22 g).

thiomorpholine 1,1-dioxide

¹H NMR (300 MHz, CDCl₃) δ 3.03 (4H, t, J=5 Hz), 3.33 (4H, t, J=5 Hz).

MS (m/z) 1.36 (M+H).

Preparation 330

To a suspension of [(5-chloro-4-mercapto-6-methyl-3-pyridinyl)oxy]aceticacid (10 g) in dichloromethane (100 mL) was added Et3N (14 mL) inice-MeOH bath. To this was added trifluoromethanesulfonic anhydride(14.3 mL) dropwise below 10° C. over 30 min. After 2 hours the mixturewas partitioned between CHCl₃ and water. The aqueous layer was extractedwith CHCl₃ twice. The combined organic layer was dried over MgSO₄ andevaporated in vacuo to give brown oil. The residue was purified bysilica gel column chromatography (silica gel, 100 mL) eluted withhexane-EtOAc=15-1 and 10-1 to give 5-chloro-3-pyridinyltrifluoromethanesulfonate (15.8 g) as a pale brown oil.

5-chloro-3-pyridinyl trifluoromethanesulfonate

¹H NMR (300 MHz, CDCl₃) δ 7.69 (1H, dd, J=4, 4 Hz), 8.52 (1H, d, J=4Hz), 8.65 (1H, d, J=4 Hz).

Preparation 331

To ethanol (66 mL) and DMF (66 mL) was added Et3N (29.4 mL),1,3-propanediylbis(diphenylphosphine) (3.48 g) and palladium acetate(1.9 g) in ice-water bath. To this was added 5-chloro-3-pyridinyltrifluoromethanesulfonate (22.1 g) at the temperature. The mixture wasstirred at 50° C. for 4 hours under CO (1 atom). The mixture waspartitioned betwwen EtOAc and water. The aqueous layer was extractedwith EtOAc. The combined organic layer was washed with water threetimes, dried over MgSO₄ and evaporated in vacuo. The residue waspurified by silica gel column chromatography (silica gel, 200 mL) elutedwith hexane-EtOAc=15-1 and 10-1 to give ethyl 5-chloronicotinate (105 g)as a pale brown oil.

ethyl 5-chloronicotinate

¹H NMR (300 MHz, CDCl₃) δ 1.42 (3H, t, J=7 Hz), 4.43 (2H, q, J=7 Hz),8.28 (1H, dd, J=3, 3 Hz), 8.74 (1H, d, J=3 Hz), 9.09 (1H, d, J=3 Hz).

Preparation 332

To 5-chloronicotinate (105 g) was added 1N NaOH (84.9 mL) at ambienttemperature. The mixture was heated at 60° C. for 1 hour. The reactionmixture was adjusted to pH 4-5 with HCl. The precipitate was filtered togive 5-chloronicotinic acid (6.9 g) a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 8.30 (1H, dd, J=3 Hz), 8.88 (1H, d, J=3 Hz),9.01 (1H, d, J=3 Hz), 1.38 (1H, br s).

5-chloronicotinic acid

H NMR (300 MHz, DMSO-d₆) δ 8.30 (1H, dd, J=3, 3 Hz), 8.88 (1H, d, J=3Hz), 9.01 (1H, d, J=3 Hz), 1.38 (1H, br s).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 332.

Preparation 333

5-methoxynicotinic acid

¹H NMR (DMSO-d₆) δ 3.87 (3H, s), 7.73 (1H, m), 8.48 (1H, d, J=3 Hz),8.65 (1H, d, J=1 Hz).

MS (ESI⁺): m/z 154 (M+H).

Preparation 334

5-pyrimidinecarboxylic acid

¹H NMR (DMSO-d₆) δ 9.20 (2H, s), 9.37 (1H, s).

MS (ESI⁺): m/z 148 (M++Na).

Preparation 335

To a solution of diisopropylamine (5.41 g) in THF (30 mL) was added 1.5M n-butyllithium hexane solution (35 mL) under dryice acetone coolingand the mixture was stirred at −78° C. for 10 minutes. To this was addedtert-butyl acetate (5.87 g) under dryice acetone cooling and the mixturewas stirred at −78° C. for 10 minutes and added dropwise to a solutionof 5-bromonicotinic acid (3.00 g) and N,N-carbonyldiimidazole (2.65 g)in THF (30 mL) under dryice acetone cooling. The mixture was stirred at−78° C. for 0.5 hour. The mixture was partitioned between ethyl acetateand aq NH₄Cl solution. The organic layer was separated, washed with aqNaHCO₃ solution and brine, dried over MgSO₄, and evaporated in vacuo.The residue was triturated with isopropyl ether to give tert-butyl3-(5-bromo-3-pyridinyl)-3-oxopropanoate as a colorless powder (3.71 g).

tert-butyl 3-(5-bromo-3-pyridinyl)-3-oxopropanoate

Enol form: ¹H NMR (CDCl₃) δ 1.54 (9H, s), 5.62 (1H, s), 8.19 (1H, m),8.72 (1H, d, J=2 Hz), 8.86 (1H, d, J=2 Hz).

Keto form: ¹H NMR (CDCl₃) δ 1.44 (9H, s), 3.90 (2H, s), 8.37 (1H, m),8.86 (1H, d, J=2 Hz), 9.03 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 300 302.

Preparation 336

To a suspension of NaH in DMF (50 mL) which was washed with hexane 3times was added methyl 5-hydroxynicotinate (10.2 g) portionwise below10° C. in an ice-water bath under nitrogen atmosphere. After 30 min,methyl iodide (4.56 mL) was added dropwise therein. The precipitateappeared and the mixture was hard to be stirred. DMF (30 mL) was added.After 20 min, the mixture was stirred at ambient temperature for 3 h.The reaction mixture was quenched with MeOH and was concentrated invacuo. To the residue was added CHCl₃, sat. NaHCO₃, and brine. Theorganic layer was separated and the aqueous layer was extracted withCHCl₃. The combined organic layer was dried over MgSO₄ and wasevaporated in vacuo. The residue was purified by flash silica gelchromatography (silica gel, 200 mL) eluted with hexane-AcOEt=5-1 and 3-1to give methyl 5-methoxynicotinate (3.47 g) as a pale brown solid.

methyl 5-methoxynicotinate

¹H NMR (CDCl₃) δ 3.91 (3H, s), 3.96 (3H, s), 7.76 (1H, m), 8.47 (1H, d,J=3 Hz), 8.83 (1H, d, J=1 Hz).

MS (ESI⁺): m/z 168 (M+H).

Preparation 337

To a solution of methyl2-bromo-4-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate (330 mg) inN,N-dimethylformamide (5 mL) was added 60% sodium hydride in oil (58.4mg) in an ice-bath over 5 miutes. After stirring for 1 hour,(aminooxy)(diphenyl)phosphine oxide (340 mg) was added portionwise over40 minutes. The resulting mixture was stirred for 1 hour in the bath.The reaction was quenched by adding water (10 mL). The mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with water (two times) and brine, dried over magnesium sulfate,and evaporated. The residue was dissolved in ethyl acetatec-hexane(1-5), and to the solution was added silica gel. The mixture wasfiltered, and the filtrate was evaporated to give methyl4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-2-bromobenzoate as anorange solid (310 mg).

methyl 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-2-bromobenzoate

¹H-NMR (CDCl₃) δ 1.29 (3H, t, J=7 Hz), 2.76 (2H, q, J=7 Hz), 3.97 (3H,s), 5.73 (2H, s, br), 5.93 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz), 7.73(1H, d, J=8 Hz), 7.84 (1H, d, J=8 Hz), 8.02 (1H, s).

Preparation 338

To a solution of dimethyl 2-bromoterephthalate (1.04 g) in methanol (10mL) was added 1 N sodium hydroxide (5.71 mL) at room temperature. Afterstirring for 1.5 hour, the reaction was quenched by adding 1 Nhydrochloric acid (7 mL). White crystals were formed. Water (10 mL) wasadded to aid crystalyzation. The crystals were collected by filtration,washed with water, and dried in the air.3-Bromo-4-(methoxycarbonyl)benzoic acid was obtained as white crystals(532 mg).

3-bromo-4-(methoxycarbonyl)benzoic acid

¹H-NMR (DMSO-d₆) δ 3.89 (3H, s), 7.87 (1H, d, J=8 Hz), 8.01 (1H, d, J=8Hz), 8.17 (1H, s).

Preparation 339

A mixture of 2-[2-(2-chloroethoxy)ethoxy]ethyl acetate (6.23 g) andsodium iodide (22.2 g) in acetone (60 mL) was refluxed for 4 hours. Themixture was further refluxed for 4 hours after adding sodium iodide(11.0 g). The solvent was evaporated off, and the residue waspartitioend between EtOAc (50 mL) and water (50 mL). The aqueous layerwas washed with 10% sodium thiosulfate and brine, dried over MgSO₄, andevaporated to give 2-[2-(2-iodoethoxy)ethoxy]ethyl acetate as a paleyellow oil (9.74 g).

2-[2-(2-iodoethoxy)ethoxy]ethyl acetate

¹H-NMR (CDCl₃) δ 2.09 (3H, s), 3.27 (2H, t, J=7 Hz), 3.65-3.78 (8H, m),4.24 (2H, m).

Preparation 340

A solution of 1-tert-butyl 7-ethyl2-[(5-methyl-3-isoxazolyl)carbonyl]heptanedioate (126 mg) intrifluoroacetic acid (1 mL) was stirred for 1.5 hour at roomtemperature. The volatile was evaporated off, and azeotroped withtoluene to give7-ethoxy-2-[(5-methyl-3-isoxazolyl)carbonyl]-7-oxoheptanoic acid as apale orange oil (106 mg).

7-ethoxy-2-[(5-methyl-3-isoxazolyl)carbonyl]-7-oxoheptanoic acid

¹H-NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.41 (2H, m), 1.65 (2H, m), 2.02(2H, m), 2.30 (2H, m), 2.50 (3H, s), 2.55 (1H, s, br), 4.10 (2H, q, J=7Hz), 4.47 (1H, t, J=7 Hz), 6.40 (1H, s).

MS (ESI⁺): m/z 296.22 (M−H) and 59352 (2M-H)

Preparation 341

To a suspension of dimethyl sulfone (5.43 g) in tetrahydrofuran (10 mL)was addded 1.59 M n-butyl lithium (363 mL) in a dryice-acetone bathunder a nitrogen atmosphere. After stirring for 0.5 hour, a solution ofmethyl methoxyacetate (2.00 g) in tetrahydrofuran (5 mL) was added. Theresulting mixture was stirred for 2 hours in the bath and allowed towarm to room temperature over 2 hours. The mixture was partitionedbetween EtOAc and 4 N hydrochloric acid. The reaction was quenched byadding 4 N hydrochloric acid in EtOAc (15 mL). The mixture waspartitioned between EtOAc (100 mL) and brine (100 mL). The aqueous layerwas washed with EtOAc (100 mL, five times). The organic layer wascombined, and the combined extracts were dried over MgSO₄, andevaporated. Flash silica gel column chromatography (EtOAc-hexane=50-200to 300-100) afforded 2-(methylsulfonyl)-1-methoxyethanone as a colorlessoil (2.24 g).

1-methoxy-3-(methylsulfonyl)acetone

¹H-NMR (CDCl₃) δ 2.99 (3H, s), 3.08 (2H, s), 3.47 (3H, s), 4.19 (2H, s).

The following compound(s) was (were) obtained in a similar manner tothat of Example 1.

EXAMPLE 392 ethyl4-[3-bromo-4-(methoxycarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate

¹H-NMR (CDCl₃) δ 0.98 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.61 (3H,s), 3.04 (2H, q, J=7 Hz), 3.98 (3H, s), 4.05 (2H, q, J=7 Hz), 6.29 (1H,d, J=5 Hz), 6.67 (1H, d, J=7 Hz), 7.44 (1H, d, J=8 Hz), 7.76 (1H, s),7.89 (1H, d, J=8 Hz).

EXAMPLE 3933-[7-ethyl-2-(methoxymethyl)-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

¹H-NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.98 (2H, q, J=7 Hz), 3.18 (3H,s), 3.45 (3H, s), 4.59 (2H, s), 6.25 (1H, d, J=5 Hz), 6.71 (1H, d, J=5Hz), 7.65 (1H, t, J=8 Hz), 7.78 (1H, d, J=8 Hz), 7.94 (1H, d, J=8 Hz),7.99 (1H, s).

MS (ESI⁺): m/z 370 (M+H)

The following compound(s) was (were) obtained in a similar manner tothat of Example 16.

EXAMPLE 3945-{4-[3-(aminocarbonyl)phenyl]-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H-NMR (CDCl₃) δ 1.02 (4H, m), 1.28 (3H, t, J=7 Hz), 1.70 (2H, m), 2.37(2H, m), 2.92 (2H, q, J=7 Hz), 5.87 (1H, d, J=5 Hz), 6.66 (1H, d, J=5Hz), 7.46-7.67 (5H, m), 7.96-8.08 (3H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 21.

EXAMPLE 395 ethyl4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 10.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.65-1.78(2H, m), 2.22 (2H, t, J=7 Hz), 2.40-2.52 (2H, m), 2.58 (3H, s), 3.03(2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.86 (1H, d, J=4 Hz), 6.53 (1H,d, J=4 Hz), 7.25 (1H, d, J=5 Hz), 7.36 (1H, s), 8.53 (1H, d, J=5 Hz).

MS (ESI⁺): m/z 386.

EXAMPLE 396 ethyl3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.30-2.39(2H, m), 2.57 (3H, s), 2.74-2.83 (2H, m), 3.03 (2H, q, J=7 Hz), 4.12(2H, q, J=7 Hz), 5.88 (1H, d, J=4 Hz), 6.55 (1H, d, J=4 Hz), 7.24 (1H,d, J=5 Hz), 7.35 (1H, s), 8.53 (1H, d, J=5 Hz).

MS (ESI⁺): m/z 372.

EXAMPLE 397 ethyl5-[2-benzyl-4-(2-chloro-4-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.30-1.50(4H, m), 2.10 (2H, t, J=7 Hz), 2.23-2.35 (2H, m), 3.04 (2H, q, J=7 Hz),4.09 (2H, q, J=7 Hz), 4.21 (2H, s), 5.88 (1H, d, J=4 Hz), 6.58 (1H, d,J=4 Hz), 7.14-7.32 (7H, m), 8.50 (1H, d, J=5 Hz).

EXAMPLE 398 methyl{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}acetate

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.42 (3H, s), 2.61 (3H, s),2.78-2.88 (2H, m), 3.03 (2H, q, J=7 Hz), 3.46-3.57 (2H, m), 3.71 (3H,s), 3.95 (2H, s), 5.87 (1H, d, J=4 Hz), 6.52 (1H, d, J=4 Hz), 7.54 (1H,s), 8.43 (1H, d, J=2 Hz), 8.53 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 368.

EXAMPLE 399ethyl[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.51 (3H,s), 3.03 (2H, q, J=7 Hz), 3.43 (2H, s), 4.12 (2H, q, J=7 Hz), 5.99 (1H,d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.94 (1H, m), 8.58 (1H, d, J=2 Hz),8.78 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 402 404.

EXAMPLE 400 ethyl3-[2-[(acetyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.16 (3H,s), 2.32-2.42 (2H, m), 2.44 (3H, s), 2.77-2.90 (2H, m), 3.03 (2H, q, J=7Hz), 4.12 (2H, q, J=7 Hz), 5.31 (2H, s), 5.96 (1H, d, J=4 Hz), 6.63 (1H,d, J=4 Hz), 7.53 (1H, s), 8.42 (1H, d, J=2 Hz), 8.55 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 410.

EXAMPLE 401 ethyl4-[2-[(acetyloxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyffolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.64-1.78(2H, m), 2.10-2.23 (2H, m), 2.17 (3H, s), 2.43 (3H, s), 2.43-2.58 (2H,m), 3.02 (2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.33 (2H, s), 5.93 (1H,d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.53 (1H, s), 8.43 (1H, s), 8.55 (1H,s).

MS (ESI⁺): m/z 424.

EXAMPLE 402 ethyl5-[2-[(acetyloxy)methyl]-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60(4H, m), 2.16 (2H, t, J=7 Hz), 2.17 (3H, s), 2.40-2.52 (2H, m), 3.03(2H, q, J=7 Hz), 4.12 (2H, q, J=7 Hz), 5.29 (2H, s), 5.88 (1H, d, J=4Hz), 6.62 (1H, d, J=4 Hz), 7.60-7.68 (3H, m), 7.75-7.83 (1H, m).

MS (ESI⁺): m/z 448.

EXAMPLE 403 ethyl4-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.65-1.82(2H, m), 2.17 (3H, s), 2.21 (2H, t, J=7 Hz), 2.45-2.63 (2H, m), 3.02(2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.33 (2H, s), 5.95 (1H, d, J=4Hz), 6.63 (1H, d, J=4 Hz), 7.90 (1H, m), 8.57 (1H, d, J=2 Hz), 8.80 (1H,d, J=2 Hz).

MS (ESI⁺): m/z 488 490.

EXAMPLE 404 ethyl3-[2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.16 (3H,s), 2.36 (2H, t, J=7 Hz), 2.77-2.95 (2H, m), 3.02 (2H, q, J=7 Hz), 4.06(2H, q, J=7 Hz), 5.31 (2H, s), 5.96 (1H, d, J=4 Hz), 6.64 (1H, d, J=4Hz), 7.88 (1H, s), 8.56 (1H, m), 8.80 (1H, m).

MS (ESI⁺): m/z 474 476.

EXAMPLE 405 ethyl3-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 0.88-1.06 (2H, m), 1.19 (3H, t, J=7 Hz), 1.15-1.36 (3H,m), 1.37 (3H, t, J=7 Hz), 1.58-1.85 (6H, m), 2.42 (2H, m), 2.43 (3H, s),2.83-2.97 (2H, m), 3.05 (2H, q, J=7 Hz), 3.38 (2H, d, J=7 Hz), 4.06 (2H,q, J=7 Hz), 4.66 (2H, s), 5.91 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz),7.52 (1H, s), 8.42 (1H, d, J=2 Hz), 8.54 (1H, d, J=2 Hz).

EXAMPLE 406 ethyl3-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}propanoate

¹H NMR (CDCl₃) δ 0.85-1.06 (2H, m), 1.20 (3H, t, J=7 Hz), 1.37 (3H, t,J=7 Hz), 1.16-1.46 (3H, m), 1.55-1.84 (6H, m), 2.43 (2H, t, J=7 Hz),2.82-3.00 (2H, m), 3.06 (2H, q, J=7 Hz), 3.37 (2H, d, J=7 Hz), 4.06 (2H,q, J=7 Hz), 4.66 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz),7.87 (1H, m), 8.55 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 528 530.

EXAMPLE 407 ethyl4-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H NMR (CDCl₃) δ0.87-1.06 (2H, m), 1.21 (3H, t, J=7 Hz), 1.37 (3H, t,J=7 Hz), 1.16-1.46 (3H, m), 1.50-1.85 (8H, m), 2.23 (2H, t, J=7 Hz),2.55-2.75 (2H, m), 3.04 (2H, q, J=7 Hz), 3.38 (2H, d, J=7 Hz), 4.08 (2H,q, J=7 Hz), 4.67 (2H, s), 5.92 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz),7.89 (1H, m), 8.56 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 542 544.

EXAMPLE 408 ethyl4-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 0.22-0.32 (2H, m), 0.53-0.65 (2H, m), 1.10-1.20 (1H,m), 1.19 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.65-1.80 (2H, m),2.14-2.30 (2H, m), 2.43 (3H, s), 2.57-2.74 (2H, m), 3.05 (2H, q, J=7Hz), 3.43 (2H, d, J=7 Hz), 4.03 (2H, q, J=7 Hz), 4.74 (2H, s), 5.90 (1H,d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.53 (1H, s), 8.43 (1H, s), 8.54 (1H,s).

MS (ESI⁺): m/z 436.

EXAMPLE 409 ethyl3-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 0.22-0.32 (2H, m), 0.54-0.63 (2H, m), 1.10-1.20 (1H,m), 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.40-2.50 (2H, m), 2.43(3H, s), 2.86-2.98 (2H, m), 3.05 (2H, q, J=7 Hz), 3.42 (2H, d, J=7 Hz),4.06 (2H, q, J=7 Hz), 4.71 (2H, s), 5.92 (1H, d, J=4 Hz), 6.60 (1H, d,J=4 Hz), 7.52 (1H, s), 8.42 (1H, s), 8.54 (1H, s).

MS (ESI⁺): m/z 422.

EXAMPLE 410 ethyl3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-methoxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.44 (2H,t, J=7 Hz), 2.82-2.98 (2H, m), 3.05 (2H, q, J=7 Hz), 3.38 (3H, s), 3.58(2H, m), 3.76 (2H, m), 4.05 (2H, q, J=7 Hz), 4.76 (2H, s), 5.93 (1H, d,J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.87 (1H, m), 8.54 (1H, s), 8.79 (1H, s).

MS (ESI⁺): m/z 490 492.

EXAMPLE 4114-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=7 Hz), 2.54 (3H, s), 3.04 (2H, q, J=7Hz), 6.39 (1H, s), 6.51 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 8.17 (1H,m), 8.76 (1H, d, J=2 Hz), 8.86 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 316 318.

EXAMPLE 412 ethyl4-[2-[(acetyloxy)methyl]-4-(5-chloro-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (300 MHz, CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz),1.70 (2H, tt, J=7, 7 Hz), 2.17 (3H, s), 2.20 (2H, t, J=7 Hz), 2.45-2.54(2H, m), 3.02 (2H, q, J=7 Hz), 4.04 (2H, q, J=7 Hz), 5.33 (2H, s), 5.94(1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.74 (1H, dd, J=2, 2 Hz), 8.53(1H, d, J=2 Hz), 8.70 (1H, d, J=2 Hz).

EXAMPLE 413 ethyl5-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (300 MHz, CDCl₃) δ 0.23-0.26 (2H, m), 0.54-0.59 (2H, m),1.07-1.16 (1H, m), 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.41-1.56(4H, m), 2.17 (2H, t, J=7 Hz), 2.53-2.64 (2H, m), 3.03 (2H, q, J=7 Hz),3.41 (2H, d, J=7 Hz), 4.09 (2H, q, J=7 Hz), 4.70 (2H, s), 5.90 (1H, d,J=5 Hz), 6.58 (1H, d, J=5 Hz), 7.72 (1H, s), 8.51 (1H, s), 8.68 (1H, s).

EXAMPLE 414 ethyl4-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H NMR (300 MHz, CDCl₃) δ 0.24 (2H, dt, J=7, 7 Hz), 0.56 (2H, dt, J=7, 7Hz), 1.07-1.15 (1H, m), 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.72(2H, tt, J=7, 7 Hz), 2.21 (2H, t, J=7 Hz), 2.55-2.66 (2H, m), 3.02 (2H,q, J=7 Hz), 3.43 (2H, d, J=7 Hz), 4.04 (2H, q, J=7 Hz), 4.73 (2H, s),5.91 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.74 (1H, dd, J=2, 2 Hz),8.52 (1H, d, J=2 Hz), 8.68 (1H, d, J=2 Hz).

EXAMPLE 415 ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (300 MHz, CDCl₃) δ 0.92 (6H, d, J=7 Hz), 1.26 (3H, t, J=7 Hz),1.34 (3H, t, J=7 Hz), 1.38-1.56 (4H, m), 1.92 (1H, qt, J=7, 7 Hz), 2.15(2H, t, J=7 Hz), 2.51-2.63 (2H, m), 3.03 (2H, q, J=7 Hz), 3.33 (2H, d,J=7 Hz), 4.09 (2H, q, J=7 Hz), 4.65 (2H, s), 5.90 (1H, d, J=7 Hz), 6.59(1H, d, J=7 Hz), 7.88 (1H, dd, J=2, 2 Hz), 8.55 (1H, d, J=2 Hz), 8.77(1H, d, J=2 Hz).

EXAMPLE 416 ethyl3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (300 MHz, CDCl₃) δ 0.92 (6H, d, J=7 Hz), 1.19 (3H, t, J=7 Hz),1.37 (3H, t, J=7 Hz), 1.91 (1H, qt, J=7, 7 Hz), 2.41 (2H, t, J=8 Hz),2.84-2.94 (2H, m), 3.03 (2H, q, J=7 Hz), 3.35 (2H, d, J=7H), 4.05 (2H,q, J=7 Hz), 4.68 (2H, s), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz),7.72 (1H, dd, J=2, 2 Hz), 8.51 (1H, d, J=2 Hz), 8.69 (1H, d, J=2 Hz).

EXAMPLE 417 ethyl3-[2-[(acetyloxy)methyl]-4-(3-chlorophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (300 MHz, CDCl₃) δ 1.19 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz),2.15 (3H, s), 2.33 (2H, t, J=8 Hz), 2.82 (2H, t, J=8 Hz), 3.02 (2H, q,J=7 Hz), 4.06 (2H, q, J=7 Hz), 5.31 (2H, s), 5.97 (1H, d, J=4 Hz), 6.61(1H, d, J=4 Hz), 7.23-7.26 (1H, m), 7.37 (1H, s), 7.44-7.46 (2H, m).

EXAMPLE 418 ethyl4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (300 MHz, CDCl₃) δ 0.92 (6H, d, J=7 Hz), 1.20 (3H, t, J=7 Hz),1.37 (3H, t, J=7 Hz), 1.71 (2H, tt, J=8, 8 Hz), 1.91 (1H, qt, J=7, 7Hz), 2.20 (2H, t, J=8 Hz), 2.56-2.66 (2H, m), 3.03 (2H, q, J=7 Hz), 3.34(2H, d, J=7 Hz), 4.05 (2H, q, J=7 Hz), 4.69 (2H, s), 5.91 (1H, d, J=5Hz), 6.60 (1H, d, J=5 Hz), 7.89 (1H, s), 8.56 (1H, d, J=2 Hz), 8.78 (1H,d, J=2 Hz).

EXAMPLE 419 2,4-bis(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazine

¹H NMR (CDCl₃) δ 1.45 (3H, t, J=7 Hz), 3.14 (2H, q, J=7 Hz), 6.66 (1H,d, J=4 Hz), 6.86 (1H, d, J=4 Hz), 6.91 (1H, s), 8.23 (1H, m), 8.48 (1H,m), 8.77 (1H, m), 8.83 (1H, m), 8.94 (1H, d, J=2 Hz), 9.18 (1H, d, J=2Hz).

EXAMPLE 420 ethyl4-[2-[(acetyloxy)methyl]-4-(3-chlorophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.19 (3H, t, J=8 Hz), 1.34 (3H, t, J=8 Hz), 1.63-1.76(2H, m), 2.10-2.22 (5H, m), 2.45-2.55 (2H, m), 3.01 (2H, q, J=8 Hz),4.04 (2H, q, J=8 Hz), 5.32 (2H, s), 5.95 (1H, d, J=5 Hz), 6.59 (1H, d,J=5 Hz), 7.21-7.29 (1H, overlappled with CDCl₃), 7.36 (1H, br s),7.38-7.46 (2H, m).

MS (ESI⁺): m/z 443 (M+H).

EXAMPLE 421 ethyl5-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=8 Hz), 1.33-1.60 (7H, m), 1.55-1.70 (2H,m), 2.17 (2H, t, J=8 Hz), 2.46-2.64 (2H, m), 3.04 (2H, d, J=8 Hz), 3.46(3H, s), 3.90 (3H, s), 4.09 (2H, q, J=8 Hz), 4.62 (2H, s), 5.93 (1H, d,J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.23 (1H, m), 8.22 (1H, d, J=1 Hz), 8.40(1H, d, J=3 Hz).

MS (ESI⁺): m/z 426 (M+H).

EXAMPLE 422 ethyl5-[7-ethyl-4-(5-methoxy-3-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=8 Hz), 1.33-1.62 (7H, m), 2.18 (2H, t,J=8 Hz), 2.38-2.49 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 3.90(3H, s), 4.08 (2H, q, J=8 Hz), 5.89 (1H, d, J=5 Hz), 6.51 (1H, d, J=5Hz), 7.21 (1H, m), 8.21 (1H, d, J=1 Hz), 8.40 (1H, d, J=3 Hz).

MS (ESI⁺): m/z 396 (M+H).

EXAMPLE 423 ethyl3-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 2.40 (2H,t, J=8 Hz), 2.81-2.96 (2H, m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 3.90(3H, s), 4.05 (2H, q, J=8 Hz), 4.65 (2H, s), 5.96 (1H, d, J=5 Hz), 6.60(1H, d, J=5 Hz), 7.21 (1H, m), 8.23 (1H, br s), 8.40 (1H, d, J=3 Hz).

MS (ESI⁺): m/z 398 (M+H).

EXAMPLE 424 ethyl4-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 1.64-1.79(2H, m), 2.14-2.24 (2H, m), 2.53-2.66 (2H, m), 3.04 (2H, d, J=8 Hz),3.47 (3H, s), 3.90 (3H, s), 4.04 (2H, q, J=8 Hz), 4.67 (2H, br s), 5.94(1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.23 (1H, m), 8.22 (1H, d, J=1Hz), 8.40 (1H, d, J=3 Hz).

MS (ESI⁺): m/z 412 (M+H).

EXAMPLE 425 ethyl5-[7-ethyl-2-(methoxymethyl)-4-(5-pyrimidinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=8 Hz), 1.30-1.62 (7H, m), 2.19 (2H, t,J=8 Hz), 2.46-2.60 (2H, m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 3.90(3H, s), 4.09 (2H, q, J=8 Hz), 4.63 (2H, s), 5.90 (1H, d, J=5 Hz), 6.61(1H, d, J=5 Hz), 8.80 (2H, s), 9.34 (1H, s).

MS (ESI⁺): m/z 397 (M+H).

EXAMPLE 426 ethyl4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.21 (3H, t, J=8 Hz), 1.37 (3H, t, J=8 Hz), 1.62-1.76(2H, m), 2.21 (2H, t, J=8 Hz), 2.49-2.67 (2H, m), 3.04 (2H, d, J=8 Hz),3.46 (3H, s), 4.06 (2H, q, J=8 Hz), 4.67 (2H, br s), 5.92 (1H, d, J=5Hz), 6.61 (1H, d, J=5 Hz), 7.74 (1H, m), 8.53 (1H, d, J=1 Hz), 8.69 (1H,d, J=2 Hz).

MS (ESI⁺): m/z 414 (M−H).

EXAMPLE 427 ethyl3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 2.40 (2H,t, J=8 Hz), 2.82-2.94 (2H, m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 4.06(2H, q, J=8 Hz), 4.65 (2H, s), 5.93 (1H, d, J=5 Hz), 6.67 (1H, d, J=5Hz), 7.73 (1H, br s), 8.51 (1H, br s), 8.70 (1H, br s).

MS (ESI⁺): m/z 402 (M+H).

EXAMPLE 428 ethyl5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=8 Hz), 1.34-1.60 (7H, m), 2.19 (2H, t,J=8 Hz), 2.47-2.64 (2H, m), 3.04 (2H, d, J=8 Hz), 3.46 (3H, s), 4.10(2H, q, J=8 Hz), 4.62 (2H, s), 5.90 (1H, d, J=5 Hz), 6.60 (1H, d, J=5Hz), 7.73 (1H, m), 8.51 (1H, br s), 8.68 (1H, br s).

MS (ESI⁺): m/z 426 (M+H).

EXAMPLE 429 methyl2-[(acetyloxy)methyl]-4-(5-bromo-3-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carboxylate

mp 122-123 deg.

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=8 Hz), 2.12 (3H, s), 3.06 (2H, t, J=8Hz), 3.61 (3H, s), 5.43 (2H, s), 6.37 (1H, d, J=5 Hz), 6.78 (1H, d, J=5Hz), 7.93 (1H, t, J=1 Hz), 8.57 (1H, d, J=1 Hz), 8.78 (1H, d, J=1 Hz).

MS (ESI⁺): m/z 432, 434 (M+H).

EXAMPLE 4302-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}ethoxy)ethylacetate

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.05 (3H, s), 2.42 (3H, s), 2.59(3H, s), 2.75 (2H, m), 3.00 (2H, q, J=7 Hz), 3.39-3.48 (4H, m), 3.54(2H, m), 3.63 (2H, m), 4.16 (2H, m), 5.86 (1H, d, J=5 Hz), 6.52 (1H, d,J=5 Hz), 7.50 (1H, m), 8.43 (1H, m), 8.52 (1H, m).

EXAMPLE 431 ethyl(2E)-4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-2-butenoate

¹H-NMR (CDCl₃) δ 1.27 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 2.49 (3H,s), 3.02 (2H, q, J=7 Hz), 3.30 (2H, m), 4.16 (2H, q, J=7 Hz), 5.58 (1H,d, J=16 Hz), 5.90 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz), 6.97 (1H, dt,J=7 and 16 Hz), 7.58 (2H, m), 7.65 (1H, s), 7.75 (1H, m).

EXAMPLE 432 ethyl4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz),1.65-1.78 (2H, m), 2.23 (2H, t, J=7 Hz), 2.54-2.72 (2H, m), 3.04 (2H, q,J=7 Hz), 3.46 (3H, s), 4.06 (2H, q, J=7 Hz), 4.66 (2H, s), 5.93 (1H, d,J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.89 (1H, m), 8.55 (1H, d, J=2 Hz), 8.77(1H, d, J=2 Hz).

MS (ESI⁺): m/z 460 462.

EXAMPLE 433 ethyl4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate

¹H NMR (CDCl₃) δ 0.99 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 2.63 (3H,s), 3.05 (2H, q, J=8 Hz), 4.07(2H, q, J=8 Hz), 6.27(1H, d, J=5 Hz), 6.70(1H, d, J=5 Hz), 7.30 (1H, dd, J=5, 1 Hz), 7.41 (1H, br s), 8.49 (1H, d,J=5 Hz).

MS (ESI⁺): m/z 344 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Example 76.

EXAMPLE 4344-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.72-1.84 (2H, m), 2.33 (2H, t,J=7 Hz), 2.47-2.57 (2H, m), 2.58 (3H, s), 3.03 (2H, q, J=7 Hz), 5.88(1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.27 (1H, m), 7.38 (1H, s), 8.53(1H, d, J=5 Hz).

MS (ESI⁻): m/z 356, MS (ESI⁺): m/z 358.

EXAMPLE 4353-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.36-2.47 (2H, m), 2.58 (3H, s),2.76-2.88 (2H, m), 3.03 (2H, q, J=7 Hz), 5.89 (1H, d, J=4 Hz), 6.55 (1H,d, J=4 Hz), 7.25 (1H, d, J=5 Hz), 7.35 (1H, s), 8.53 (1H, d, J=5 Hz).

EXAMPLE 4364-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.30-1.42 (2H, m), 1.35 (9H, s),1.63-1.76 (2H, m), 2.22-2.37 (4H, m), 3.93 (1H, d, J=17 Hz), 4.12 (2H,q, J=7 Hz), 4.29 (1H, d, J=17 Hz), 7.22 (2H, d, J=8 Hz), 7.26-7.36 (4H,m), 7.50 (1H, s), 8.42 (1H, d, J=5 Hz).

MS (ESI⁻): m/z 418, MS (ESI⁺): m/z 420.

EXAMPLE 4373-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 1.36 (3H, t, J=7 Hz), 2.06 (2H, t, J=7 Hz), 2.78 (2H,t, J=7 Hz), 3.04 (2H, q, J=7 Hz), 5.99 (1H, d, J=4 Hz), 6.67 (1H, d, J=4Hz), 7.28 (1H, d, J=5 Hz), 7.41 (1H, s), 7.45-7.55 (5H, m), 8.53 (1H, d,J=5 Hz).

MS (ESI⁻): m/z 404, MS (ESI⁺): m/z 406.

EXAMPLE 4385-[2-benzyl-4-(2-chloro-4-pyridinyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.16-1.32 (2H, m), 1.39 (3H, t, J=7 Hz), 1.38-1.53 (2H,m), 2.15 (2H, t, J=7 Hz), 2.30-2.40 (2H, m), 3.06 (2H, q, J=7 Hz), 4.21(2H, s), 5.88 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.18-7.35 (7H, m),8.49 (1H, d, J=5 Hz).

MS (ESI⁻): m/z 446, MS (ESI⁺): m/z 448.

EXAMPLE 439{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}aceticacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.44 (3H, s), 2.59 (3H, s),2.74-2.92 (2H, m), 3.02 (2H, q, J=7 Hz), 3.54-3.66 (2H, m), 3.93 (2H,m), 5.82 (1H, d, J=4 Hz), 6.53 (1H, d, J=4 Hz), 7.63 (1H, s), 8.52 (1H,s), 8.56 (1H, s).

EXAMPLE 440{2-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}aceticacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.80 (2H, t, J=7 Hz), 3.03 (2H,q, J=7 Hz), 3.20 (2H, t, J=7 Hz), 3.72 (3H, s), 6.01 (1H, d, J=4 Hz),6.67 (1H, d, J=4 Hz), 7.42 (1H, d, J=5 Hz), 7.45-7.60 (6H, m), 8.57 (1H,d, J=5 Hz).

EXAMPLE 441[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]aceticacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.55 (3H, s), 2.97-3.10 (2H, m),3.30-3.62 (2H, m), 5.97 (1H, m), 6.57 (1H, m), 8.03 (1H, s), 8.69 (1H,s), 8.77 (1H, s).

MS (ESI⁺): m/z 374 376.

EXAMPLE 4423-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.33-2.50 (2H, m), 2.42 (3H, s),2.80-3.00 (2H, m), 3.06 (2H, q, J=7 Hz), 4.72 (2H, s), 4.83 (2H, s),5.92 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.36 (2H, d, J=7 Hz), 7.55(1H, s), 8.41 (1H, s), 8.44 (2H, d, J=7 Hz), 8.53 (1H, s).

MS (ESI⁺): m/z 429 431.

EXAMPLE 4433-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.42 (3H, s), 2.40-2.55 (2H, m),2.83-3.12 (2H, m), 3.03 (2H, q, J=7 Hz), 4.84 (2H, s), 4.91 (2H, m),5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.57 (1H, s), 8.42 (1H, s),8.48-8.55 (3H, m), 8.76 (1H, s).

MS (ESI⁺): m/z 432.

EXAMPLE 4443-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.43 (3H, s), 2.50-2.60 (2H, m),2.88-3.05 (2H, m), 3.03 (2H, q, J=7 Hz), 4.81 (2H, s), 4.87 (2H, s),5.82 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.27 (1H, m), 7.48 (1H, d,J=8 Hz), 7.56 (1H, s), 7.77 (1H, t, J=8 Hz), 8.43 (1H, s), 8.54 (2H, m).

EXAMPLE 4454-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H NMR (CDCl₃) δ 1.40 (3H, t, J=7 Hz), 1.70-1.85 (2H, m), 2.16-2.31 (2H,m), 2.44 (3H, s), 2.53-2.83 (2H, m), 3.05 (2H, q, J=7 Hz), 4.72 (2H, s),4.83-4.98 (2H, m), 5.92 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.30 (2H,d, J=7 Hz), 7.57 (1H, s), 8.38-8.55 (4H, m).

MS (ESI⁻): m/z 443, MS (ESI⁺): m/z 445.

EXAMPLE 4465-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 2.20 (2H, t,J=7 Hz), 2.52-2.68 (2H, m), 3.04 (2H, q, J=7 Hz), 4.69 (2H, s), 4.78(2H, s), 5.93 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.35 (2H, d, J=6Hz), 7.88 (1H, m), 8.54 (2H, d, J=6 Hz), 8.55 (1H, m), 8.79 (1H, m).

EXAMPLE 4475-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.40-1.62 (4H, m), 2.17 (2H, t,J=7 Hz), 2.50-2.67 (2H, m), 3.04 (2H, q, J=7 Hz), 4.69 (2H, s), 4.76(2H, s), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.32-7.38 (1H, m),7.77 (1H, d, J=8 Hz), 7.88 (1H, m), 8.55 (2H, m), 8.65 (1H, m), 8.78(1H, m).

MS (ESI⁻): m/z 521 523, MS (ESI⁺): m/z 523 525.

EXAMPLE 4485-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.48-1.67 (4H, m), 2.26 (2H, t,J=7 Hz), 2.53-2.75 (2H, m), 3.03 (2H, q, J=7 Hz), 4.82 (2H, s), 4.83(2H, s), 5.90 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.26-7.34 (1H, m),7.53 (1H, d, J=8 Hz), 7.75-7.83 (1H, m), 7.87 (1H, m), 8.55 (1H, d, J=2Hz), 8.62 (1H, m), 8.77 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 523 525.

EXAMPLE 4495-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.45-1.64 (4H, m), 2.23 (2H, t,J=7 Hz), 2.53-2.72 (2H, m), 3.03 (2H, q, J=7 Hz), 4.83 (2H, s), 4.87(2H, s), 5.93 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.88 (1H, m), 8.53(3H, m), 8.77 (2H, m).

MS (ESI⁻): m/z 522 524, MS (ESI⁺): m/z 524 526.

EXAMPLE 4504-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=7 Hz), 1.69-1.84 (2H, m), 2.27 (2H, t,J=7 Hz), 2.56-2.80 (2H, m), 3.02 (2H, q, J=7 Hz), 4.73 (2H, s), 4.92(2H, m), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.31 (2H, d, J=6Hz), 7.90 (1H, m), 8.46 (2H, d, J=6 Hz), 8.57 (1H, d, J=2 Hz), 8.78 (1H,d, J=2 Hz).

MS (ESI⁻): m/z 507 509, MS (ESI⁺): m/z 509 511.

EXAMPLE 4514-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.66-1.83 (2H, m), 2.26 (2H, t,J=7 Hz), 2.53-2.77 (2H, m), 3.04 (2H, q, J=7 Hz), 4.71 (2H, s), 4.86(2H, m), 5.92 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.33 (1H, m), 7.78(1H, d, J=8 Hz), 7.90 (1H, m), 8.50 (1H, m), 8.56 (1H, d, J=2 Hz), 8.60(1H, s), 8.78 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 509 511.

EXAMPLE 4524-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.70-1.85 (2H, m), 2.23-2.34 (2H,m), 2.57-2.76 (2H, m), 3.03 (2H, q, J=7 Hz), 4.81 (2H, s), 4.90 (2H, m),5.91 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.28 (1H, m), 7.49 (1H, d,J=7 Hz), 7.77 (1H, t, J=8 Hz), 7.88 (1H, m), 8.55 (1H, d, J=2 Hz), 8.57(1H, m), 8.74 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 509 511.

EXAMPLE 4534-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H NMR (CDCl₃) δ 0.22 (2H, m), 0.57 (2H, m), 1.07-1.22 (1H, m), 1.37(3H, t, J=7 Hz), 1.72-1.87 (2H, m), 2.28 (2H, t, J=7 Hz), 2.58-2.77 (2H,m), 3.03 (2H, q, J=7 Hz), 3.41 (2H, d, J=7 Hz), 4.72 (2H, s), 5.92 (1H,d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.93 (1H, m), 8.56 (1H, d, J=2 Hz),8.77 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 470 472, MS (ESI⁺): m/z 472 474.

EXAMPLE 4544-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.68-1.83 (2H, m), 2.27 (2H, t,J=7 Hz), 2.56-2.78 (2H, m), 3.03 (2H, q, J=7 Hz), 4.84 (2H, s), 4.92(2H, m), 5.94 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.91 (1H, m), 8.51(2H, m), 8.56 (1H, d, J=2 Hz), 8.76 (2H, m).

MS (ESI⁻): m/z 508 510, MS (ESI⁺): m/z 510 512.

EXAMPLE 4553-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=7 Hz), 2.38 (2H, t, J=7 Hz), 2.83-2.98(2H, m), 3.07 (2H, q, J=7 Hz), 4.74 (2H, s), 4.83 (2H, s), 5.95 (1H, d,J=4 Hz), 6.65 (1H, d, J=4 Hz), 7.38 (2H, d, J=6 Hz), 7.88 (1H, s), 8.43(2H, d, J=6 Hz), 8.55 (1H, s), 8.78 (1H, s).

MS (ESI⁻): m/z 493 495, MS (ESI⁺): m/z 495 497.

EXAMPLE 4564-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-hydroxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.68-1.83 (2H, m), 2.28 (2H, t,J=7 Hz), 2.53-2.76 (2H, m), 3.02 (2H, q, J=7 Hz), 3.75 (2H, m), 3.79(2H, m), 4.78 (2H, s), 5.93 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.90(1H, s), 8.56 (1H, s), 8.78 (1H, s).

MS (ESI⁻): m/z 460 462, MS (ESI⁺): m/z 462 464.

EXAMPLE 4573-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 0.88-1.06 (2H, m), 1.10-1.36 (3H, m), 1.37 (3H, t, J=7Hz), 1.58-1.85 (6H, m), 2.42 (3H, s), 2.48-2.60 (2H, m), 2.80-3.02 (2H,m), 3.04 (2H, q, J=7 Hz), 3.39 (2H, d, J=7 Hz), 4.67 (2H, m), 5.89 (1H,d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.57 (1H, s), 8.42 (1H, s), 8.53 (1H,s).

MS (ESI⁻): m/z 434, MS (ESI⁺): m/z 436.

EXAMPLE 4583-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (CDCl₃) δ 0.88-1.05 (2H, m), 1.10-1.36 (3H, m), 1.37 (3H, t, J=7Hz), 1.56-1.83 (6H, m), 2.51 (2H, t, J=7 Hz), 2.80-3.07 (2H, m), 3.06(2H, q, J=7 Hz), 3.37 (2H, d, J=7 Hz), 4.67 (2H, s), 5.93 (1H, d, J=4Hz), 6.63 (1H, d, J=4 Hz), 7.89 (1H, m), 8.55 (1H, s), 8.79 (1H, s).

MS (ESI⁻): m/z 498 500, MS (ESI⁺): m/z 500 502.

EXAMPLE 4594-{4-(5-bromo-3-pyridinyl)-2-[(cyclohexylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H NMR (CDCl₃) δ 0.86-1.03 (2H, m), 1.10-1.35 (3H, m), 1.37 (3H, t, J=7Hz), 1.60-1.82 (8H, m), 2.28 (2H, t, J=7 Hz), 2.55-2.76 (2H, m), 3.05(2H, q, J=7 Hz), 3.36 (2H, d, J=7 Hz), 4.67 (2H, s), 5.92 (1H, d, J=4Hz), 6.62 (1H, d, J=4 Hz), 7.91 (1H, m), 8.55 (1H, d, J=2 Hz), 8.76 (1H,d, J=2 Hz).

MS (ESI⁻): m/z 512 514, MS (ESI⁺): m/z 514 516.

EXAMPLE 4604-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (CDCl₃) δ 0.22-0.32 (2H, m), 0.55-0.63 (2H, m), 1.10-1.22 (1H,m), 1.37 (3H, t, J=7 Hz), 1.73-1.86 (2H, m), 2.20-2.35 (2H, m), 2.46(3H, s), 2.55-2.86 (2H, m), 3.04 (2H, q, J=7 Hz), 3.43 (2H, d, J=7 Hz),4.70-4.85 (2H, m), 5.88 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.62 (1H,s), 8.42 (1H, s), 8.46 (H, s).

MS (ESI⁺): m/z 408.

EXAMPLE 4613-[2-[(cyclopropylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 0.23-0.35 (2H, m), 0.54-0.65 (2H, m), 1.08-1.24 (1H,m), 1.37 (3H, t, J=7 Hz), 2.43 (3H, s), 2.50-2.65 (2H, m), 2.70-3.05(2H, m), 3.04 (2H, q, J=7 Hz), 3.44 (2H, d, J=7 Hz), 4.74 (2H, s), 5.89(1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.56 (1H, s), 8.42 (1H, s), 8.53(1H, s).

MS (ESI⁻): m/z 392, MS (ESI⁺): m/z 394.

EXAMPLE 4623-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-methoxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.48-2.62 (2H, m), 2.83-3.02 (2H,m), 3.02 (2H, q, J=7 Hz), 3.37 (3H, s), 3.60 (2H, m), 3.73 (2H, m), 4.75(2H, s), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.89 (1H, m), 8.55(1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 460 462, MS (ESI⁺): m/z 462 464.

EXAMPLE 4635-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(4-morpholinylcarbonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.35-1.65 (4H, m), 2.23 (2H, t,J=7 Hz), 2.40-2.56 (2H, m), 3.02 (2H, q, J=7 Hz), 3.48-3.57 (4H, m),3.60-3.78 (4H, m), 5.33 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4Hz), 7.89 (1H, m), 8.56 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz).

EXAMPLE 4645-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.45-1.65 (4H, m), 2.22 (2H, t,J=7 Hz), 2.42-2.57 (2H, m), 2.97 (6H, s), 3.03 (2H, q, J=7 Hz), 5.30(2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.89 (1H, s), 8.54(1H, s), 8.78 (1H, s).

MS (ESI⁺): m/z 503 505.

EXAMPLE 4655-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(1-pyrrolidinylcarbonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoicacid

¹H NMR (CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.40-1.63 (4H, m), 1.82-1.97 (4H,m), 2.23 (2H, t, J=7 Hz), 2.43-2.58 (2H, m), 3.03 (2H, q, J=7 Hz),3.37-3.52 (4H, m), 5.31 (2H, s), 5.93 (1H, d, J=4 Hz), 6.60 (1H, d, J=4Hz), 7.88 (1H, m), 8.54 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 527 529, MS (ESI⁺): m/z 529 531.

EXAMPLE 4665-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[({[methyl(phenyl)amino]carbonyl}oxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.40-1.58 (4H, m), 2.18 (2H, t,J=7 Hz), 2.32-2.53 (2H, m), 3.04 (2H, q, J=7 Hz), 3.37 (3H, s), 5.36(2H, s), 5.92 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.16-7.40 (5H, m),7.87 (1H, s), 8.52 (1H, s), 8.79 (1H, s).

EXAMPLE 4674-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(4-morpholinylcarbonyl)oxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)butanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.65-1.84 (2H, m), 2.27 (2H, t,J=7 Hz), 2.45-2.68 (2H, m), 3.04 (2H, q, J=7 Hz), 3.53 (4H, m), 3.69(4H, m), 5.36 (2H, s), 5.95 (1H, d, J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.91(1H, m), 8.55 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

EXAMPLE 4684-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.66-1.82 (2H, m), 2.27 (2H, t,J=7 Hz), 2.46-2.68 (2H, m), 2.97 (6H, s), 3.04 (2H, q, J=7 Hz), δ 33(2H, s), 5.94 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.92 (1H, m), 8.56(1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

EXAMPLE 4693-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 1.36 (3H, t, J=7 Hz), 2.45 (2H, t, J=7 Hz), 2.82-2.96(2H, m), 2.97 (6H, s), 3.03 (2H, q, J=7 Hz), 5.33 (2H, s), 5.96 (1H, d,J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.89 (1H, m), 8.55 (1H, d, J=2 Hz), 8.78(1H, d, J=2 Hz).

MS (ESI⁻): m/z 473 475, MS (ESI⁺): m/z 475 477.

EXAMPLE 4705-{4-(5-bromo-3-pyridinyl)-2-[(1,1-dioxido-4-thiomorpholinyl)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.42-1.56 (4H, m), 2.26(2H, t, J=7 Hz), 2.48-2.61 (2H, m), 3.01 (2H, q, J=7 Hz), 3.10 (4H, t,J=6 Hz), 3.19 (4H, t, J=6 Hz), 3.85 (2H, s), 5.92 (1H, d, J=4 Hz), 6.61(1H, d, J=4 Hz), 7.89 (1H, dd, J=2, 2 Hz), 8.56 (1H, d, J=2 Hz), 8.78(1H, d, J=2 Hz).

MS (m/z) 550 (M+H).

EXAMPLE 4715-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.43-1.58 (4H, m), 2.24(2H, t, J=7 Hz), 2.49-2.61 (2H, m), 2.66 (4H, t, J=4 Hz), 2.86 (4H, t,J=4 Hz), 3.02 (2H, q, J=7 Hz), 3.68 (2H, s), 5.89 (1H, d, J=5 Hz), 6.58(1H, d, J=5 Hz), 7.90 (1H, s), 8.56 (1H, s), 8.79 (1H, s).

MS (m/z) 518 (M+H).

EXAMPLE 4725-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.34 (3H, t, J=7 Hz), 1.41-1.57 (4H, m), 2.21(2H, t, J=6 Hz), 2.43-2.57 (2H, m), 2.80-2.84 (4H, m), 2.91-3.00 (6H,m), 3.65 (2H, s), 3.83 (2H, m), 5.88 (1H, d, J=5 Hz), 6.57 (1H, d, J=5Hz), 7.88 (1H, s), 8.55 (1H, s), 8.77 (1H, s).

MS (m/z) 545 (M+H).

EXAMPLE 4734-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.72 (2H, tt, J=7, 7Hz), 2.26 (2H, t, J=7 Hz), 2.53-2.68 (6H, m), 2.87-2.90 (4H, m), 3.02(2H, q, J=7 Hz), 3.72 (2H, s), 5.91 (1H, d, J=4 Hz), 6.59 (1H, d, J=4Hz), 7.78 (1H, dd, J=2, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.68 (1H, d, J=2Hz).

MS (m/z) 460 (M+H).

EXAMPLE 4744-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.73 (2H, tt, J=7, 7Hz), 2.25 (2H, t, J=7 Hz), 2.57-2.73 (2H, m), 3.04 (2H, q, J=7 Hz), 4.72(2H, s), 4.89 (2H, s), 5.93 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.31(2H, d, J=6 Hz), 7.76 (1H, dd, J=2, 2 Hz), 8.46 (2H, d, J=6 Hz), 8.53(1H, d, J=2 Hz), 8.67 (1H, d, J=2 Hz).

MS (m/z) 465 (M+H).

EXAMPLE 4754-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.73 (2H, tt, J=7, 7Hz), 2.26 (2H, t, J=7 Hz), 2.54-2.72 (6H, m), 3.03 (2H, q, J=7 Hz),3.66-3.73 (6H, m), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.79 (1H,s), 8.53 (1H, s), 8.67 (1H, s).

MS (m/z) 443 (M+H).

EXAMPLE 4765-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (300 MHz, CDCl₃) δ 0.24 (2H, dt, J=7, 7 Hz), 0.57 (2H, dt, J=7, 7Hz), 1.07-1.17 (1H, m), 1.38 (3H, t, J=7 Hz), 1.45-1.61 (4H, m), 2.23(2H, t, J=7 Hz), 2.52-2.66 (2H, m), 3.02 (2H, q, J=7 Hz), 3.41 (2H, d,J=7 Hz), 4.70 (2H, s), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.74(1H, dd, J=2, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.68 (1H, d, J=2 Hz).

MS (m/z) 442 (M+H).

EXAMPLE 4774-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H NMR (300 MHz, CDCl₃) δ 0.23 (2H, dt, J=6, 6 Hz), 0.56 (2H, dt, J=6, 6Hz), 1.05-1.17 (1H, m), 1.37 (3H, t, J=7 Hz), 1.75 (2H, tt, J=7, 7 Hz),2.28 (2H, t, J=7 Hz), 2.57-2.70 (2H, m), 3.03 (2H, q, J=7 Hz), 3.42 (2H,d, J=7 Hz), 4.73 (2H, s), 5.91 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz),7.77 (1H, dd, J=2, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.66 (1H, d, J=2 Hz).

MS (m/z) 428 (M+H).

EXAMPLE 4785-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (300 MHz, CDCl₃) δ 0.93 (6H, d, J=7 Hz), 1.37 (3H, t, J=7 Hz),1.42-1.59 (4H, m), 1.92 (1H, qt, J=7, 7 Hz), 2.24 (2H, t, J=7 Hz),2.48-2.69 (2H, m), 3.03 (2H, q, J=7 Hz), 3.33 (2H, d, J=7 Hz), 4.66 (2H,s), 5.91 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.90 (1H, dd, J=2, 2Hz), 8.56 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz).

MS (m/z) 489 (M+H).

EXAMPLE 4793-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (300 MHz, CDCl₃) δ 0.92 (6H, d, J=7 Hz), 1.37 (3H, t, J=7 Hz),1.91 (1H, qt, J=7, 7 Hz), 2.49 (2H, t, J=8 Hz), 2.82-2.98 (2H, m), 3.03(2H, q, J=7 Hz), 3.35 (2H, d, J=7 Hz), 4.69 (2H, s), 5.92 (1H, d, J=4Hz), 6.61 (1H, d, J=4 Hz), 7.72 (1H, dd, J=2, 2 Hz), 851 (1H, d, J=2Hz), 8.69 (1H, d, J=2 Hz).

MS (m/z) 416 (M+H).

EXAMPLE 4803-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7 Hz), 2.55 (2H, t, J=8 Hz),2.66 (4H, br s), 2.79-2.97 (2H, m), 3.02 (2H, q, J=7 Hz), 3.70-3.74 (6H,m), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.90 (1H, dd, J=2, 2Hz), 8.55 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz).

MS (m/z) 474 (M+H).

EXAMPLE 4814-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.73 (2H, tt, J=7, 7Hz), 2.26 (2H, t, J=7 Hz), 2.57-2.70 (6H, m), 3.02 (2H, q, J=7 Hz), 3.69(6H, m), 5.90 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.93 (1H, dd, J=2,2 Hz), 8.57 (1H, d, J=2 Hz), 8.77(1H, d, J=2 Hz).

MS (m/z) 488 (M+H).

EXAMPLE 4824-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H NMR (300 MHz, CDCl₃) δ 0.54-0.60 (2H, m), 0.74-0.79 (2H, m), 1.38(3H, t, J=7 Hz), 1.65 (2H, tt, J=6, 6 Hz), 2.21 (2H, t, J=6 Hz),2.45-2.55 (2H, m), 3.03 (2H, q, J=7 Hz), 4.30 (2H, s), 5.04 (1H, br s),5.93 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.73 (1H, dd, J=2, 2 Hz),8.52 (1H, d, J=2 Hz), 8.69(1H, d, J=2 Hz).

MS (m/z) 413 (M+H).

EXAMPLE 4835-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-phenoxyethyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.42-1.56 (4H, m), 2.22(2H, br s), 2.34-2.48 (2H, m), 3.03 (2H, q, J=7 Hz), 3.38-3.43 (2H, brs), 4.23-4.50 (4H, m), 5.93 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz),6.89-6.97 (3H, m), 7.23-7.30 (2H, m), 7.85 (1H, s), 8.52 (1H, s), 8.78(1H, s).

MS (m/z) 552 (M+H).

EXAMPLE 4845-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-hydroxyethyl)(methyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.34-1.54 (4H, m),2.15-2.26 (2H, m), 2.33-2.52 (2H, m), 2.98 (2H, q, J=7 Hz), 3.16 (3H,s), 3.59-3.72 (2H, m), 3.99-4.10 (2H, m), 4.70 (2H, s), 5.94 (1H, d, J=4Hz), 6.59 (1H, d, J=4 Hz), 7.85 (1H, s), 8.51 (1H, s), 8.73 (1H, s).

MS (m/z) 490 (M+H).

EXAMPLE 4855-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-piperidinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.39-1.51 (6H, m),1.62-1.71 (4H, m), 2.19 (2H, t, J=6 Hz), 2.52-2.65 (2H, m), 2.78-2.91(4H, m), 3.10 (2H, q, J=7 Hz), 3.65 (2H, s), 5.89 (1H, d, J=5 Hz), 6.58(1H, d, J=5 Hz), 7.88 (1H, s), 8.55 (1H, s), 8.76 (1H, s).

MS (m/z) 500 (M+H).

EXAMPLE 4863-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.52 (2H, t, J=8 Hz),2.68 (4H, t, J=5 Hz), 2.81-2.95 (6H, m), 3.02 (2H, q, J=7 Hz), 3.74 (2H,s), 5.92 (1H, d, J=5 Hz), 6.61 (1H, d, J=5 Hz), 7.89 (1H, dd, J=2, 2Hz), 8.55 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz).

MS (m/z) 490 (M+H).

EXAMPLE 4873-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}pyrrolo[1,2-b]pyridazin-3-yl)propanoicacid

¹H NMR (300 MHz, DMSO-d₆) δ 1.32 (3H, t, J=7 Hz), 2.40-2.56 (12H, m),2.58-2.65 (2H, m), 2.94 (2H, q, J=7 Hz), 3.52 (2H, t, J=5 Hz), 3.67 (2H,s), 5.83 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz), 8.25 (1H, dd, J=2, 2Hz), 8.63 (1H, d, J=2 Hz), 8.86 (1H, d, J=2 Hz).

MS (m/z) 517 (M+H).

EXAMPLE 4884-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(isobutoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (300 MHz, CDCl₃) δ 0.91 (6H, d, J=7 Hz), 1.37 (3H, t, J=7 Hz),1.74 (2H, tt, J=8, 8 Hz), 1.91 (1H, qt, J=7, 7 Hz), 2.27 (2H, t, J=8Hz), 2.56-2.73 (2H, m), 3.03 (2H, q, J=7 Hz), 3.33 (2H, d, J=7 Hz), 4.68(2H, s), 5.92 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.92 (1H, dd, J=7,7 Hz), 8.56 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz).

MS (m/z) 475 (M+H).

EXAMPLE 4895-[2-{[2-(benzylamino)-2-oxoethoxy]methyl}-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.33 (3H, t, J=7 Hz), 1.39-1.60 (4H, m), 2.15 (2H, t,J=7 Hz), 2.42 (3H, s), 2.40-2.58 (2H, m), 2.95 (2H, q, J=7 Hz), 4.19(2H, s), 4.50 (2H, d, J=7 Hz), 4.75 (2H, m), 5.91 (1H, d, J=4 Hz), 6.59(1H, d, J=4 Hz), 7.07 (1H, br), 7.22-7.34 (5H, m), 7.54 (1H, s), 8.40(1H, s), 8.53 (1H, s).

MS (ESI⁻): m/z 513, MS (ESI⁺): m/z 515.

EXAMPLE 4905-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(phenylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoicacid

¹H NMR (CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.23-1.60 (4H, m), 2.19 (2H, t,J=7 Hz), 2.28-2.46 (2H, m), 2.42 (3H, s), 2.97 (2H, q, J=7 Hz), 4.37(2H, m), 5.89 (1H, d, J=4 Hz), 5.90 (1H, m), 6.57 (1H, d, J=4 Hz),7.42-7.53 (4H, m), 7.90 (2H, d, J=8 Hz), 8.34 (1H, s), 8.53 (1H, s).

MS (ESI⁻): m/z 505, MS (ESI⁺): m/z 507.

EXAMPLE 4915-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-pyrrolidinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.35 (3H, t, J=7 Hz), 1.39-1.57 (4H, m),1.79-1.88 (4H, m), 2.18 (2H, t, J=7 Hz), 2.84-2.89 (6H, m), 3.00 (2H, q,J=7 Hz), 3.89-4.02 (2H, m), 5.88 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz),7.87 (1H, s), 8.55 (1H, s), 8.75 (1H, s).

MS (m/z) 486 (M+H).

EXAMPLE 4923-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=8 Hz), 2.39-2.48 (2H, m), 2.83-2.94 (2H,m), 3.03 (2H, q, J=8 Hz), 3.45 (3H, s), 4.65 (2H, s), 5.95 (1H, d, J=5Hz), 6.60 (1H, d, J=5 Hz), 7.24 (1H, m), 7.35 (1H, br s), 7.40-7.46 (2H,m).

MS (ESI⁺): m/z 373 (M+H).

EXAMPLE 4934-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=8 Hz), 1.64-1.78 (2H, m), 2.24 (2H, t,J=8 Hz), 2.56-2.66 (2H, m), 3.04 (2H, q, J=8 Hz), 3.45 (3H, s), 4.65(2H, s), 5.94 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.21-7.29 (1H,overlappled with CDCl₃), 7.36 (1H, br s), 7.39-7.46 (2H, m).

MS (ESI⁺): m/z 387 (M+H).

EXAMPLE 4945-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-phenyl-1-piperazinyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.41-1.61 (4H, m), 2.22(2H, t, J=7 Hz), 2.49-2.67 (2H, m), 2.76 (4H, t, J=5 Hz), 3.03 (2H, q,J=7 Hz), 3.20 (4H, t, J=5 Hz), 3.73 (2H, s), 5.89 (1H, d, J=5 Hz), 6.58(1H, d, J=5 Hz), 6.85 (1H, dd, J=8, 8 Hz), 6.93 (2H, J=8 Hz), 7.25 (2H,J=8 Hz), 7.90 (1H, dd, J=2, 2 Hz), 8.56 (1H, d, J=2 Hz), 8.77 (1H, d,J=2 Hz).

EXAMPLE 4955-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-methoxyethyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.28 (3H, t, J=7 Hz), 1.32-1.43 (4H, m),2.03-2.17 (2H, m), 2.23-2.41 (2H, m), 2.49-2.88 (2H, m), 2.98 (2H, q,J=7 Hz), 3.37 (3H, s), 3.89-3.99 (2H, m), 4.51 (2H, s), 5.91 (1H, d, J=5Hz), 6.57 (1H, d, J=5 Hz), 7.82 (1H, s), 8.47 (1H, s), 8.72 (1H, s).

EXAMPLE 4965-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

mp 111-112° C.

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=8 Hz), 1.41-1.60 (4H, m), 2.21 (2H, brt, J=8 Hz), 2.30-2.70 (2H, m), 3.04 (2H, d, J=8 Hz), 3.46 (3H, s), 3.90(3H, s), 4.63 (2H, br d, J=5 Hz), 5.92 (1H, d, J=5 Hz), 6.58 (2H, d, J=8Hz), 7.25 (1H, m), 8.22 (1H, d, J=1 Hz), 8.40 (1H, d, J=3 Hz).

MS (ESI⁺): m/z 398 (M+H).

EXAMPLE 4975-[7-ethyl-4-(5-methoxy-3-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

mp 133-134° C.

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=8 Hz), 1.40-1.62 (7H, m), 2.24 (2H, t,J=8 Hz), 2.35-2.49 (2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 3.89(3H, s), 5.87 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.23 (1H, m), 8.20(1H, d, J=1 Hz), 8.39 (1H, d, J=3 Hz).

MS (ESI⁺): m/z 369 (M+H).

EXAMPLE 4983-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

mp 164-165° C.

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=8 Hz), 2.44-2.54 (2H, m), 2.80-3.00 (2H,m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 3.89 (3H, s), 4.66 (2H, br s),5.95 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.25 (1H, m), 8.22 (1H, d,J=1 Hz), 8.38 (1H, d, J=3 Hz).

MS (ESI⁺): m/z 370 (M+H).

EXAMPLE 4994-[7-ethyl-2-(methoxymethyl)-4-(5-methoxy-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

mp 140-141° C.

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=8 Hz), 1.68-1.82 (2H, m), 2.25 (2H, t,J=8 Hz), 2.52-2.75 (2H, m), 3.04 (2H, d, J=8 Hz), 3.46 (3H, s), 3.92(3H, s), 4.65 (2H, br d, J=7 Hz), 5.94 (1H, d, J=5 Hz), 6.59 (1H, d, J=5Hz), 7.29 (1H, m), 8.23 (1H, d, J=1 Hz), 8.37 (1H, d, J=3 Hz).

MS (ESI⁺): m/z 384 (M+H).

EXAMPLE 5005-[7-ethyl-2-(methoxymethyl)-4-(5-pyrimidinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=8 Hz), 1.40-1.64 (4H, m), 2.25 (2H, t,J=8 Hz), 2.49-2.61 (2H, m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 4.65(2H, s), 5.91 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz), 8.82 (2H, s), 9.32(H, s).

MS (ESI⁺): m/z 369 (M+H).

EXAMPLE 5014-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

mp 112-113° C.

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=8 Hz), 1.66-1.79 (2H, m), 2.28 (2H, t,J=8 Hz), 2.52-2.71 (2H, m), 3.05 (2H, d, J=8 Hz), 3.46 (3H, s), 4.66(2H, br s), 5.92 (1H, d, J=5 Hz), 6.61 (1H, d, J=5 Hz), 7.77 (1H, m),8.53 (1H, d, J=1 Hz), 8.67 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 388 (M+H).

EXAMPLE 5023-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

mp 159-160° C.

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=8 Hz), 2.47 (2H, br t, J=8 Hz),2.79-2.98 (2H, m), 3.04 (2H, d, J=8 Hz), 3.47 (3H, s), 4.66 (2H, s),5.93 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.74 (1H, m), 8.51 (1H, d,J=1 Hz), 8.68 (1H, d, J=3 Hz).

MS (ESI⁺): m/z 374, 376 (M+H).

EXAMPLE 5035-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

mp 118-119° C.

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=8 Hz), 1.40-1.62 (7H, m), 2.24 (2H, t,J=8 Hz), 2.45-2.64 (2H, m), 3.04 (2H, d, J=8 Hz), 3.45 (3H, s), 4.63(2H, s), 5.91 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.74 (1H, m), 8.51(1H, d, J=1 Hz), 8.67 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 402, 404 (M+H).

EXAMPLE 5044-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4H-1,2,4-triazol-4-ylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H-NMR (CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.60 (2H, m), 2.32 (2H, m), 2.46(2H, m), 3.01 (2H, q, J=7 Hz), 5.75 (2H, m), 5.97 (1H, d, J=5 Hz), 6.66(1H, d, J=5 Hz), 7.87 (1H, m), 7.97 (1H, s), 8.53 (1H, s), 8.65 (1H, s),8.69 (1H, s).

EXAMPLE 5054-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H-NMR (CDCl₃) δ 0.56 (2H, m), 0.75 (2H, m), 1.38 (3H, t, J=7 Hz), 1.65(2H, m), 2.21 (2H, m), 2.50 (2H, m), 3.01 (2H, q, J=7 Hz), 3.27 (3H,br), 4.29 (2H, s), 5.93 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.98 (1H,m), 8.55 (1H, m), 8.78 (1H, m).

MS (ESI⁺) m/z: 457 and 459 (M+H)

EXAMPLE 5064-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.68 (2H, m), 2.31 (2H, m), 2.53(2H, m), 2.98 (2H, q, J=7 Hz), 3.77 (2H, m), 4.42 (2H, t, J=7 Hz), 4.67(2H, m), 5.94 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.89(1H, m), 8.55(1H, m), 8.78 (1H, m).

EXAMPLE 5072-bromo-4-[3-(ethoxycarbonyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzoicacid

¹H-NMR (CDCl₃) δ 1.00 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.62 (3H,s), 3.04 (2H, q, J=7 Hz), 4.06 (2H, q, J=7 Hz), 6.29 (1H, d, J=5 Hz),6.68 (1H, d, J=5 Hz), 7.49 (2H, dd, J=2 and 8 Hz), 7.82 (1H, d, J=2 Hz),8.07 (1H, d, J=8 Hz).

MS (ESI⁺) m/z: 431 and 433 (M+H)

EXAMPLE 5085-[4-(3-cyanophenyl)-7-ethyl-2-(phenoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H-NMR (CDCl₃) δ 1.25-1.49 (7H, m), 2.15 (2H, m), 2.54 (2H, m), 3.02(2H, q, J=7 Hz), 5.23 (2H, s), 5.86 (1H, d, J=5 Hz), 6.60 (1H, d, J=5Hz), 6.98 (1H, t, J=8 Hz), 7.06 (2H, d, J=8 Hz), 7.28 (2H, t, J=8 Hz),7.60 (2H, m), 7.67 (1H, s), 7.77 (1H, m).

EXAMPLE 5095-[4-(3-cyanophenyl)-7-ethyl-2-(3-methyl-2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H-NMR (CDCl₃) δ 1.14-1.28 (4H, m), 1.37 (3H, t, J=7 Hz), 2.01 (2H, t,J=7 Hz), 2.23 (3H, s), 2.40 (2H, m), 3.02 (2H, q, J=7 Hz), 5.92 (1 J, d,J=5 Hz) (6.64 (1H, d, J=5 Hz), 6.94 (1 J, d, J=5 Hz), 7.33 (1H, d, J=5Hz), 7.57-7.66 (2H, m), 7.73-7.76 (2H, m).

EXAMPLE 510(2E)-4-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-2-butenoicacid

¹H-NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.55 (3H, s), 3.03 (2H, q, J=7Hz), 3.09 (2H, d, J=7 Hz), 5.45 (1H, dt, J=7 and 16 Hz), 6.05 (1H, d,J=5 Hz), 6.25 (1H, d, J=16 Hz), 6.57 (1H, d, J=5 Hz), 7.55 (1H, t, J=8Hz), 7.66+−7.72 (3H, m).

MS (ESI⁺): m/z 345 (M+H)

EXAMPLE 5114-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.68-1.84 (2H, m), 2.28 (2H, t,J=7 Hz), 2.56-2.74 (2H, m), 3.03 (2H, q, J=7 Hz), 3.46 (3H, s), 4.66(2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.92 (1H, m), 8.57(1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 430 432, MS (ESI⁺): m/z 432 434.

The following compound(s) was (were) obtained in a similar manner tothat of Example 159.

EXAMPLE 512 ethyl4-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.35-1.45(2H, m), 1.88 (2H, t, J=7 Hz), 2.43-2.55 (2H, m), 3.03 (2H, q, J=7 Hz),4.12 (2H, q, J=7 Hz), 5.98 (1H, d, J=4 Hz), 6.65 (1H, d, J=4 Hz), 7.33(1H, d, J=5 Hz), 7.42-7.55 (6H, m), 8.55 (1H, d, J=5 Hz).

MS (ESI⁺): m/z 448.

EXAMPLE 513 ethyl3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.09 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.98-2.08(2H, m), 2.75-2.85 (2H, m), 3.03 (2H, q, J=7 Hz), 3.92 (2H, q, J=7 Hz),6.00 (1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.32 (1H, d, J=5 Hz), 7.42(1H, s), 7.43-7.57 (5H, m), 8.55 (1H, d, J=5 Hz).

MS (ESI⁺): m/z 434.

EXAMPLE 514 methyl{2-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]ethoxy}acetate

¹H NMR (CDCl₃) δ 1.36 (3H, t, J=7 Hz), 2.73-2.85 (2H, t, J=7 Hz), 3.03(2H, t, J=7 Hz), 3.15 (2H, t, J=7 Hz), 3.74 (2H, s), 4.09 (3H, s), 6.02(1H, d, J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.39 (1H, m), 7.42-7.60 (6H, m),8.53 (1H, d, J=5 Hz).

MS (ESI⁺): m/z 450.

EXAMPLE 515 ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-(3-methyl-2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H-NMR (CDCl₃) δ 1.09-1.26 (7H, m), 1.36 (3H, t, J=7 Hz), 1.93 (2H, t,J=7 Hz), 2.23 (3H, s), 2.39 (2H, m), 3.03 (2H, q, J=7 Hz), 4.03 (2H, q,J=7 Hz), 5.93 (1H, d, J=5 Hz), 6.64 (1H, d, J=7 Hz), 6.96 (1H, d, J=5Hz), 7.33 (1H, d, J=5 Hz), 7.60-7.67 (2H, m), 7.72-7.79 (2H, m).

EXAMPLE 516 methyl5-[4-(3-cyanophenyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H-NMR (CDCl₃) δ 1.21-1.47 (7H, m), 2.04 (2H, t, J=7 Hz), 2.60 (2H, m),3.05 (2H, q, J=7 Hz), 3.61 (3H, s), 5.37 (1H, d, J=5 Hz), 6.63 (1H, d,J=5 Hz), 7.13 (1H, m), 7.36 (1H, m), 7.44 (1H, m), 7.62-7.78 (4H, m).

EXAMPLE 517 ethyl3-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H-NMR (CDCl₃) δ 1.08 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.98 (2H,m), 2.75 (2H, m), 3.02 (2H, q, J=7 Hz), 3.89 (2H, q, J=7 Hz), 5.93 (1H,d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.41-7.55 (5H, m), 7.57-7.78 (4H, m).

MS (ESI⁺): m/z 424 (M+H)

EXAMPLE 518 ethyl5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H-NMR (CDCl₃) δ 1.02-1.25 (7H, m), 1.37 (3H, t, J=7 Hz), 1.88 (2H, t,J=7 Hz), 2.43 (2H, m), 3.01 (2H, q, J=7 Hz), 4.00 (2H, q, J=7 Hz), 5.96(1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.29 (1H, m), 7.37-7.54 (8H, m).

MS (ESI⁺): m/z 461

EXAMPLE 5194-(5-bromo-3-pyridinyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-3-carbonitrile

¹H NMR (CDCl₃) δ 1.42 (3H, t, J=8 Hz), 3.12 (2H, t, J=8 Hz), 6.65 (1H,d, J=5 Hz), 6.94 (1H, d, J=5 Hz), 7.51-7.59 (3H, m), 7.83-7.91 (2H, m),8.19 (1H, m), 8.85-8.92 (2H, m).

MS (ESI⁺): m/z 403, 405 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Example 175.

EXAMPLE 5205-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.36-1.57 (4H, m), 2.16 (2H, t,J=7 Hz), 2.51-2.62 (2H, m), 3.03 (2H, q, J=7 Hz), 4.69 (2H, s), 4.78(2H, s), 5.87 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.35 (2H, d, J=5Hz), 7.61 (2H, d, J=5 Hz), 7.67 (1H, s), 7.77 (1H, m), 8.54 (2H, d, J=5Hz).

MS (ESI⁻): m/z 467, MS (ESI⁺): m/z 469.

EXAMPLE 5215-{4-[3-(aminocarbonyl)phenyl]-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.47-1.68 (4H, m), 2.15-2.40 (2H,m), 2.40-2.56 (1H, m), 2.82-2.96 (1H, m), 3.05 (2H, q, J=7 Hz), 4.68(2H, s), 4.72 (1H, d, J=17 Hz), 4.93 (1H, d, J=17 Hz), 5.83 (1H, d, J=4Hz), 6.58 (1H, d, J=4 Hz), 7.31 (2H, d, J=5 Hz), 7.39 (1H, br), 7.45(1H, d, J=8 Hz), 7.58 (1H, t, J=8 Hz), 7.69 (1H, br), 7.77 (1H, br),7.98 (1H, d, J=8 Hz), 8.57 (2H, d, J=5 Hz).

MS (ESI⁻): m/z 485, MS (ESI⁺): m/z 487.

EXAMPLE 5225-{4-(3-cyanophenyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.30-1.57 (4H, m), 2.18 (2H, m),2.48-2.65 (2H, m), 3.03 (2H, q, J=7 Hz), 4.83 (2H, s), 4.85 (2H, s),5.86 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.61 (2H, d, J=5 Hz), 7.68(1H, s), 7.77 (1H, m), 8.53 (2H, d, J=5 Hz), 8.76 (1H, s).

MS (ESI⁻): m/z 468, MS (ESI⁺): m/z 470.

EXAMPLE 5235-{4-(3-cyanophenyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.38-1.57 (4H, m), 2.15 (2H, t,J=7 Hz), 2.49-2.62 (2H, m), 3.04 (2H, q, J=7 Hz), 4.69 (2H, s), 4.76(2H, s), 5.85 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.33 (1H, m), 7.62(2H, m), 7.67 (1H, s), 7.73-7.82 (2H, m), 8.53 (1H, d, J=5 Hz), 8.67(1H, s).

MS (ESI⁻): m/z 467, MS (ESI⁺): m/z 469.

EXAMPLE 5245-[4-(3-cyanophenyl)-7-ethyl-2-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H-NMR (CDCl₃) δ 1.34-1.52 (7H, m), 2.17 (2H, t, J=7 Hz), 2.53 (3H, s),2.77 (2H, m), 3.03 (2H, q, J=7 Hz), 5.89 (1H, d, J=5 Hz), 6.54 (1H, s),6.67 (1H, d, J=5 Hz), 7.63 (2H, m), 7.68 (1H, s), 7.78 (1H, m).

EXAMPLE 5255-[4-(3-cyanophenyl)-7-ethyl-2-(2-thienyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H-NMR (CDCl₃) δ 1.23-1.42 (7H, m), 2.07 (2H, t, J=7 Hz), 2.58 (2H, m),3.03 (2H, q, J=7 Hz), 5.87 (1H, d, J=5 hz), 6.56 (1H, d, J=5 Hz), 7.13(1H, m), 7.36 (1H, m), 7.43 (1H, d, J=5 Hz), 7.62 (2H, m), 7.70 (1H, s),7.76 (1H, m).

EXAMPLE 5263-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H-NMR (CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.99 (2H, m), 2.75 (2H, m), 3.00(2H, q, J=7 Hz), 5.93 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.42-7.55(5H, m), 7.57-7.78 (4H, m).

EXAMPLE 5275-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H-NMR (CDCl₃) δ 1.03-1.25 (4H, m), 1.36 (3H, t, J=7 Hz), 1.90 (2H, t,J=7 Hz), 2.41 (2H, m), 3.00 (2H, q, J=7 Hz), 5.97 (1H, d, J=5 Hz), 6.59(1H, d, J=5 Hz), 7.28 (1H, m), 7.35-7.54 (8H, m).

MS (ESI⁺): m/z 433 (M+H)

The following compound(s) was (were) obtained in a similar manner tothat of Example 180.

EXAMPLE 528 ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-(5-methyl-3-isoxazolyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H-NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.32-1.46 (5H, m), 1.72 (2H, m),2.10 (2H, t, J=7 Hz), 2.54 (3H, s), 2.78 (2H, m), 3.03 (2H, q, J=7 Hz),4.06 (2H, q, J=7 Hz), 5.89 (1H, d, J=5 Hz), 6.54 (1H, s), 6.66 (1H, d,J=5 Hz), 7.62 (2H, m), 7.67 (1H, s), 7.77 (1H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 176.

EXAMPLE 529 ethyl4-[4-(aminocarbonyl)-3-bromophenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate

¹H-NMR (CDCl₃) δ 1.03 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 2.60 (3H,s), 3.03 (2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 5.83 (1H, s, br), 6.19(1H, s, br), 6.28 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz), 7.46 (1H, d,J=8 Hz), 7.72 (1H, s), 7.77 (1H, d, J=8 Hz).

The following compound(s) was (were) obtained in a similar manner tothat of Example 184.

EXAMPLE 5303-[2-(cyclopentylamino)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

¹H-NMR (CDCl₃) δ 1.36 (3H, t, J=7 Hz), 1.51-1.80 (6H, m), 2.15 (2H, m),2.96 (2H, q, J=7 Hz), 3.05 (3H, s), 4.27 (1H, m), 5.94 (1H, d, J=5 Hz),6.47-6.53 (2H, m), 7.53-7.59 (3H, m), 7.74 (1H, m).

EXAMPLE 5313-[7-ethyl-2-(methylamino)-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.94-3.07 (8H, m), 5.95 (1H, d,J=5 Hz), 6.50 (2H, m), 7.54-7.59 (3H, m), 7.74 (1H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 225.

EXAMPLE 532(2R,3R,4S,5S,6R)-2-({3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoyl}amino)-6-{1[(2,2-dimethylpropanoyl)oxy]methyl}tetrahydro-2H-pyran-3,4,5-triyltris(2,2-dimethylpropanoate)

¹H-NMR (CDCl₃) δ 1.07 (9H, s), 1.11 (9H, s), 1.16 (9H, s), 1.18 (9H, s),1.37 (3H, t, J=7 Hz), 2.23 (2H, m), 2.84 (2H, m), 3.03 (2H, q, J=7 Hz),3.48 (3H, s), 3.91-4.21 (3H, m), 4.62-4.67 (2H, m), 5.00-5.26 (3H, m),5.43 (2H, m), 5.91 (1H, d, J=5 Hz), 6.55 (1H, m, br), 6.62 (1H, d, J=5Hz), 7.84 (1H, m), 8.51 (1H, m), 8.77 (1H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 226.

EXAMPLE 533[4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol

¹H-NMR (CDCl₃) δ 1.40 (3H, t, J=7 Hz), 2.53 (1H, t, J=7 Hz), 3.07 (2H,q, J=7 Hz), 4.48 (2H, m), 6.23 (1H, d, J=5 Hz), 6.62 (1H, m), 6.71 (1H,d, J=5 Hz), 7.10 (1H, d, J=5 Hz), 7.46-7.52 (3H, m), 7.61 (1H, m), 7.64(1H, m).

EXAMPLE 534[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methanol

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=8 Hz), 3.05 (2H, q, J=8 Hz), 3.45-3.55(4H, m), 4.40 (2H, br d, J=7 Hz), 4.77 (2H, br s), 6.22 (1H, d, J=5 Hz),6.70 (1H, d, J=5 Hz), 8.11 (1H, m), 8.74 (1H, br s), 8.80 (1H, d, J=2Hz).

MS (ESI⁺): m/z 302 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Example 227.

EXAMPLE 535(2R,3S,4S,5R,6R)-2-[(acetyloxy)methyl]-6-({5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentyl}oxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate

¹H-NMR (CDCl₃) δ 0.82-1.18 (6H, m), 1.37 (3H, t, J=7 Hz), 1.92-2.17(14H, m), 2.35 (2H, m), 3.01 (2H, q, J=7 Hz), 3.16 (1H, m), 3.62 (1H,m), 3.85 (1H, m), 4.11 (2H, m), 4.10 (2H, m), 4.30 (1H, d, J=8.1 Hz),4.96 (1H, m), 5.11 (1H, m), 5.35 (1H, m), 5.90 (1H, d, J=5 Hz), 6.62(1H, d, J=5 Hz), 7.44-7.53 (5H, m), 7.60-7.80 (4H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 228.

EXAMPLE 536 ethyl3-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.19 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 2.33 (2H,t, J=7 Hz), 2.43 (3H, s), 2.70-2.82 (2H, m), 3.04 (2H, q, J=7 Hz), 3.71(1H, t, J=5 Hz), 4.05 (2H, q, J=7 Hz), 4.89 (2H, d, J=5 Hz), 5.98 (1H,d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.52 (1H, s), 8.42 (1H, d, J=2 Hz),8.56 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 368.

EXAMPLE 537 ethyl4-[7-ethyl-2-(hydroxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.62-1.78(2H, m), 2.16-2.28 (2H, m), 2.36-2.53 (2H, m), 2.44 (3H, s), 3.06 (2H,q, J=7 Hz), 3.86 (1H, t, J=7 Hz), 4.12 (2H, q, J=7 Hz), 4.90 (2H, m),5.96 (1H, d, J=4 Hz), 6.60 (1H, d, J=4 Hz), 7.53 (1H, s), 8.44 (1H, s),8.56 (1H, s).

MS (ESI⁺): m/z 382.

EXAMPLE 538 ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.46-1.65(4H, m), 2.16 (2H, t, J=7 Hz), 2.32-2.44 (2H, m), 3.04 (2H, q, J=7 Hz),4.12 (2H, q, J=7 Hz), 4.86 (2H, s), 5.91 (1H, d, J=4 Hz), 6.60 (1H, d,J=4 Hz), 7.58-7.68 (3H, m), 7.75-7.82 (1H, m).

MS (ESI⁺): m/z 406.

EXAMPLE 539 ethyl4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.25 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.64-1.79(2H, m), 2.23 (2H, t, J=7 Hz), 2.42-2.53 (2H, m), 3.04 (2H, q, J=7 Hz),4.10 (2H, q, J=7 Hz), 4.91 (2H, s), 5.97 (1H, d, J=4 Hz), 6.62 (1H, d,J=4 Hz), 7.89 (1H, m), 8.56 (1H, d, J=2 Hz), 8.80 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 446 448.

EXAMPLE 540 ethyl3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.32 (2H,m), 2.68-2.90 (2H, m), 3.03 (2H, q, J=7 Hz), 4.10 (2H, m), 4.89 (2H, s),6.03 (1H, m), 6.65 (1H, m), 7.90 (1H, m), 8.58 (1H, m), 8.83 (1H, m).

MS (ESI⁺): m/z 432 434.

EXAMPLE 541 ethyl4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (300 MHz, CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz),1.67 (2H, tt, J=7, 7 Hz), 2.20 (2H, t, J=7 Hz), 2.37-2.79 (2H, m), 3.04(2H, q, J=7 Hz), 3.77 (1H, t, J=4 Hz), 4.07 (2H, q, J=7 Hz), 4.91 (2H,d, J=4 Hz), 5.96 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.73 (1H, dd,J=2, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.70 (1H, d, J=2 Hz).

EXAMPLE 542 ethyl3-[4-(3-chlorophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (300 MHz, CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz),2.31 (2H, t, J=8 Hz), 2.85 (2H, t, J=8 Hz), 3.04 (2H, q, J=7 Hz),3.69-3.75 (1H, br s), 4.06 (2H, q, J=7 Hz), 4.88 (2H, s), 6.00 (1H, d,J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.23-7.26 (1H, m), 7.36 (1H, s),7.44-7.46 (2H, m).

EXAMPLE 543 ethyl4-[4-(3-chlorophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.21 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 1.57 (3H,s), 1.59-1.74 (2H, m), 2.20 (2H, t, J=8 Hz), 2.37-2.47 (2H, m), 3.03(2H, q, J=8 Hz), 3.84 (1H, t, J=5 Hz), 4.06 (2H, q, J=8 Hz), 4.39 (2H,d, J=5 Hz), 5.32 (2H, s), 5.96 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz),7.21-7.29 (1H, overlappled with CDCl₃), 736 (1H, br s), 7.39-7.47 (2H,m).

EXAMPLE 5449-(5-bromo-3-pyridinyl)-6-ethyl-1H,3H-furo[3,4-e]pyrrolo[1,2-b]pyridazin-1-one

¹H NMR (CDCl₃) δ 1.42 (3H, t, J=8 Hz), 3.11 (2H, q, J=8 Hz), 5.32 (2H,s), 6.87 (1H, d, J=5 Hz), 6.99 (1H, d, J=5 Hz), 8.20 (1H, m), 8.83-8.87(2H, m).

MS (ESI⁺): m/z 358, 360 (M+H).

4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazine-3-carboxylicacid

¹H NMR (CDCl₃-CD3OD) δ 1.40 (3H, t, J=8 Hz), 3.09 (2H, q, J=8 Hz), 4.93(2H, s), 6.34 (1H, d, J=5 Hz), 6.79 (1H, d, J=5 Hz), 7.96 (1H, m), 8.55(1H, br s), 8.73 (1H, br s).

MS (ESI⁺): m/z 376, 378 (M+H).

EXAMPLE 5453-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]-N-[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]propanamide

¹H-NMR (DMSO-d₆) δ 1.30 (3H, t, J=7 Hz), 2.21 (1H, m), 2.96 (2H, q, J=7Hz), 3.25-3.45 (8H, m), 3.66 (1H, m), 4.40 (1H, m), 4.55-4.67 (5H, m),4.75 (1H, m), 5.85 (1H, d, J=5 Hz), 6.66 (1H, d, J=5 Hz), 8.23 (1H, m),8.33 (1H, d, br, J=7 Hz), 8.61 (1H, m), 8.84 (1H, m).

EXAMPLE 5463-[7-ethyl-2-phenyl-3-(5-{[(2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}pentyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

¹H-NMR (CDCl₃) δ 0.85-1.38 (6H, m), 1.46 (3H, t, J=7 Hz), 2.13 (2H, m),2.38 (2H, m), 2.65 (1H, m), 2.73 (1H, m), 3.02 (2H, q, J=7 Hz), 3.23(1H, m), 3.48-3.70 (4H, m), 3.804.01 (3H, m), 4.13 (1H, m), 5.90 (1H, d,J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.42-7.55 (5H, m), 7.60-7.79 (4H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 235.

EXAMPLE 547N-(2-aminoethyl)-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanamide

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.29 (2H, m), 2.72-3.07 (6H, m),333 (2H, q, J=7 Hz), 3.49 (3H, s), 4.68 (2H, s), 5.93 (1H, d, J=5 Hz),6.06 (1H, m, br), 6.62 (1H, d, J=5 Hz), 7.89 (1H, m), 8.55 (1H, m), 8.77(1H, m).

MS (ESI⁺) m/z: 460 and 462 (M+H)

The following compound(s) was (were) obtained in a similar manner tothat of Example 268.

EXAMPLE 548 ethyl3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate

¹H NMR (CDCl₃) δ 1.15 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.37 (2H,t, J=7 Hz), 2.43 (3H, s), 2.86-3.01 (2H, m), 3.03 (2H, q, J=7 Hz), 3.99(2H, q, J=7 Hz), 4.68 (2H, s), 4.81 (2H, s), 5.95 (1H, d, J=4 Hz), 6.62(1H, d, J=4 Hz), 7.27 (2H, d, J=7 Hz), 7.51 (1H, s), 8.43 (1H, s), 8.56(1H, s), 8.57 (2H, d, J=7 Hz).

MS (ESI⁺): m/z 459.

EXAMPLE 549 ethyl3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate

¹H NMR (CDCl₃) δ 1.16 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.39 (2H,t, J=7 Hz), 2.43 (3H, s), 2.88-3.03 (2H, m), 3.04 (2H, q, J=7 Hz), 4.01(2H, q, J=7 Hz), 4.83 (2H, s), 4.90 (2H, s), 5.94 (1H, d, J=4 Hz), 6.63(1H, d, J=4 Hz), 7.53 (1H, s), 8.42 (1H, m), 8.48-8.55 (3H, m), 8.76(1H, s).

MS (ESI⁺): m/z 460.

EXAMPLE 550 ethyl3-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate

¹H NMR (CDCl₃) δ 1.15 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.40 (2H,t, J=7 Hz), 2.42 (3H, s), 2.88-3.00 (2H, m), 3.03 (2H, q, J=7 Hz), 3.99(2H, q, J=7 Hz), 4.79 (2H, s), 4.86 (2H, s), 5.92 (1H, d, J=4 Hz), 6.60(1H, d, J=4 Hz), 7.16-7.23 (1H, m), 7.45-7.53 (2H, m), 7.68 (1H, m),8.42 (1H, m), 8.53 (2H, m).

MS (ESI⁺): m/z 459.

EXAMPLE 551 ethyl4-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H NMR (CDCl₃) δ 1.18 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.60-1.80(2H, m), 2.13-2.25 (2H, m), 2.43 (3H, s), 2.53-2.76 (2H, m), 3.03 (2H,q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 4.68 (2H, s), 4.83 (2H, m), 5.92 (1H,d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.27 (2H, d, J=5 Hz), 7.53 (1H, s),8.42 (1H, s), 8.53 (1H, s), 8.55 (2H, d, J=5 Hz).

MS (ESI⁺): m/z 473.

EXAMPLE 552 ethyl5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.35-1.57(4H, m), 2.11 (2H, t, J=7 Hz), 2.53-2.65 (2H, m), 3.03 (2H, q, J=7 Hz),4.03 (2H, q, J=7 Hz), 4.67 (2H, s), 4.78 (2H, s), 5.87 (1H, d, J=4 Hz),6.61 (1H, d, J=4 Hz), 7.28 (2H, d, J=5 Hz), 7.61 (2H, m), 7.66 (1H, s),7.78 (1H, m), 8.58 (2H, d, J=5 Hz).

MS (ESI⁺): m/z 497.

EXAMPLE 553 ethyl5-{4-(3-cyanophenyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.35-1.58(4H, m), 2.11 (2H, t, J=7 Hz), 2.55-2.65 (2H, m), 3.03 (2H, q, J=7 Hz),4.10 (2H, q, J=7 Hz), 4.82 (2H, s), 4.86 (2H, s), 5.86 (1H, d, J=4 Hz),6.60 (1H, d, J=4 Hz), 7.62 (2H, m), 7.67 (1H, s), 7.78 (1H, m), 8.51(2H, m), 8.74 (1H, s).

MS (ESI⁺): m/z 498.

EXAMPLE 554 ethyl5-{4-(3-cyanophenyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 1.32-1.66(4H, m), 2.10 (2H, t, J=7 Hz), 2.48-2.60 (2H, m), 3.03 (2H, q, J=7 Hz),4.08 (2H, q, J=7 Hz), 4.66 (2H, s), 4.75 (2H, s), 5.86 (1H, d, J=4 Hz),6.61 (1H, d, J=4 Hz), 7.28 (1H, m), 7.58-7.63 (2H, m), 7.66 (1H, s),7.66-7.80 (2H, m), 8.54 (1H, m), 8.62 (1H, m).

MS (ESI⁺): m/z 497.

EXAMPLE 555 ethyl5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.62(4H, m), 2.16 (2H, t, J=7 Hz), 2.53-2.71 (2H, m), 3.05 (2H, q, J=7 Hz),4.09 (2H, q, J=7 Hz), 4.67 (2H, s), 4.78 (2H, s), 5.93 (1H, d, J=4 Hz),6.63 (1H, d, J=4 Hz), 7.31 (2H, d, J=5 Hz), 7.88 (1H, m), 8.56 (1H, d,J=2 Hz), 8.58 (2H, d, J=5 Hz), 8.79 (1H, d, J=2 Hz).

EXAMPLE 556 ethyl5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.40 (3H, t, J=7 Hz), 1.30-1.60(4H, m), 2.15 (2H, t, J=7 Hz), 2.50-2.68 (2H, m), 3.06 (2H, q, J=7 Hz),4.12 (2H, q, J=7 Hz), 4.68 (2H, s), 4.78 (2H, s), 5.95 (1H, m), 6.63(1H, m), 7.24-7.38 (1H, m), 7.75 (1H, m), 7.89 (1H, m), 8.58 (2H, s),8.64 (1H, s), 8.80 (1H, s).

MS (ESI⁺): m/z 551 553.

EXAMPLE 557 ethyl5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.24 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.58(4H, m), 2.12 (2H, t, J=7 Hz), 2.53-2.68 (2H, m), 3.03 (2H, q, J=7 Hz),4.10 (2H, q, J=7 Hz), 4.78 (2H, s), 4.84 (2H, s), 5.92 (1H, d, J=4 Hz),6.62 (1H, d, J=4 Hz), 7.22 (1H, m), 7.48 (1H, d, J=8 Hz), 7.68-7.75 (1H,m), 7.88 (1H, m), 8.57 (2H, m), 8.78 (1H, d, J=2 Hz).

EXAMPLE 558 ethyl5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.40-1.62(4H, m), 2.15 (2H, t, J=7 Hz), 2.53-2.72 (2H, m), 3.05 (2H, q, J=7 Hz),4.08 (2H, q, J=7 Hz), 4.82 (2H, s), 4.86 (2H, s), 5.94 (1H, d, J=4 Hz),6.63 (1H, d, J=4 Hz), 7.88 (1H, m), 8.52 (2H, m), 8.55 (1H, d, J=2 Hz),8.74 (1H, m), 8.79 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 552 554.

EXAMPLE 559 ethyl4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H NMR (CDCl₃) δ 1.19 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.60-1.80(2H, m), 2.22 (2H, t, J=7 Hz), 2.55-2.74 (2H, m), 3.05 (2H, q, J=7 Hz),4.06 (2H, q, J=7 Hz), 4.69 (2H, s), 4.83 (2H, s), 5.96 (1H, d, J=4 Hz),6.63 (1H, d, J=4 Hz), 7.30 (2H, d, J=6 Hz), 7.88 (1H, m), 8.56 (2H, d,J=6 Hz), 8.57 (1H, m), 8.80 (1H, m).

MS (ESI⁺): m/z 537 539.

EXAMPLE 560 ethyl4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.55-1.82(2H, m), 2.18 (2H, t, J=7 Hz), 2.52-2.72 (2H, m), 3.05 (2H, q, J=7 Hz),4.05 (2H, q, J=7 Hz), 4.68 (2H, s), 4.83 (2H, s), 5.94 (1H, d, J=4 Hz),6.63 (1H, d, J=4 Hz), 7.28 (1H, m), 7.73 (1H, d, J=8 Hz), 7.88 (1H, m),8.54 (2H, m), 8.62 (1H, s), 8.79 (1H, s)

EXAMPLE 561 ethyl4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.63-1.82(2H, m), 2.18 (2H, t, J=7 Hz), 2.55-2.75 (2H, m), 3.06 (2H, q, J=7 Hz),4.00 (2H, q, J=7 Hz), 4.80 (2H, s), 4.88 (2H, s), 5.93 (1H, d, J=4 Hz),6.62 (1H, d, J=4 Hz), 7.22 (1H, m), 7.48 (1H, d, J=8 Hz), 7.71 (1H, t,J=8 Hz), 7.89 (1H, m), 8.55 (2H, m), 8.78 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 537 539.

EXAMPLE 562 ethyl4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H NMR (CDCl₃) δ 0.25 (2H, m), 0.60 (2H, m), 1.08-1.22 (1H, m), 1.22(3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.69-1.82 (2H, m), 2.21 (2H, t,J=7 Hz), 2.56-2.72 (2H, m), 3.03 (2H, q, J=7 Hz), 3.42 (2H, d, J=7 Hz),4.04 (2H, q, J=7 Hz), 4.73 (2H, s), 5.91 (1H, d, J=4 Hz), 6.59 (1H, d,J=4 Hz), 7.89 (1H, m), 8.56 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 500 502.

EXAMPLE 563 ethyl4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H NMR (CDCl₃) δ 1.19 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 1.70-1.82(2H, m), 2.23 (2H, t, J=7 Hz), 2.56-2.76 (2H, m), 3.06 (2H, q, J=7 Hz),4.04 (2H, q, J=7 Hz), 4.84 (2H, s), 4.95 (2H, m), 5.94 (1H, d, J=4 Hz),6.63 (1H, d, J=4 Hz), 7.89 (1H, m), 8.50 (2H, m), 8.56 (1H, s), 8.74(1H, s), 8.79 (1H, m).

MS (ESI⁺): m/z 538 540.

EXAMPLE 564 ethyl3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoate

¹H NMR (CDCl₃) δ 1.16 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.41 (2H,t, J=7 Hz), 2.85-3.07 (2H, m), 3.06 (2H, q, J=7 Hz), 4.02 (2H, q, J=7Hz), 4.68 (2H, s), 4.81 (2H, s), 5.95 (1H, d, J=4 Hz), 6.65 (1H, d, J=4Hz), 7.31 (2H, d, J=6 Hz), 7.87 (1H, m), 8.55 (1H, m), 8.56 (2H, d, J=6Hz), 8.79 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 523 525.

EXAMPLE 565 ethyl4-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)butanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.46-1.93(8H, m), 2.21 (2H, t, J=7 Hz), 2.55-2.76 (2H, m), 3.02 (2H, q, J=7 Hz),3.46-3.56 (1H, m), 3.60-3.68 (1H, m), 3.74-3.82 (2H, m), 3.83-3.96 (2H,m), 4.03 (2H, q, J=7 Hz), 4.63 (1H, m), 4.77 (2H, s), 5.91 (1H, d, J=4Hz), 6.60 (1H, d, J=4 Hz), 7.89 (1H, m), 8.56 (1H, d, J=2 Hz), 8.78 (1H,d, J=2 Hz).

EXAMPLE 566 ethyl4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H NMR (300 MHz, CDCl₃) δ 1.19 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz),1.70 (2H, t, J=7 Hz), 2.19 (2H, t, J=7 Hz), 2.55-2.67 (2H, m), 3.04 (2H,q, J=7 Hz), 4.03 (2H, q, J=7 Hz), 4.69 (2H, s), 4.83 (2H, s), 5.94 (1H,d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.29 (2H, d, J=6 Hz), 7.73 (1H, dd,J=2, 2 Hz), 8.52 (1H, d, J=2 Hz), 8.58 (2H, d, J=6 Hz), 8.69 (1H, d, J=2Hz).

EXAMPLE 567 ethyl3-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=8 Hz), 1.37 (3H, t, J=8 Hz), 2.33-2.44(2H, m), 2.84-2.94 (2H, m), 3.03 (2H, q, J=8 Hz), 3.45 (3H, s), 4.05(2H, q, J=8 Hz), 4.64 (2H, s), 5.94 (1H, d, J=5 Hz), 6.58 (1H, d, J=5Hz), 7.21-7.29 (1H, overlappled with CDCl₃), 7.36 (1H, br s), 7.38-7.46(2H, m).

EXAMPLE 568 ethyl4-[4-(3-chlorophenyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=8 Hz), 1.37 (3H, t, J=8 Hz), 1.62-1.78(2H, m), 2.14-2.28 (2H, m), 2.53-2.66 (2H, m), 3.04 (2H, q, J=8 Hz),3.46 (3H, s), 4.04 (2H, q, J=8 Hz), 4.65 (2H, s), 5.93 (1H, d, J=5 Hz),6.58 (1H, d, J=5 Hz), 7.21-7.29 (1H, overlappled with CDCl₃), 7.36 (1H,br s), 7.39-7.46 (2H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 272.

EXAMPLE 569 ethyl5-{4-(5-bromo-3-pyridinyl)-2-[(1,1-dioxido-4-thiomorpholinyl)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz),1.39-1.53 (4H, m), 2.19 (2H, t, J=7 Hz), 2.50-2.61 (2H, m), 3.00 (2H, q,J=7 Hz), 3.10 (4H, t, J=6 Hz), 3.21 (4H, t, J=6 Hz), 3.85 (2H, s), 4.10(2H, q, J=7 Hz), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.88 (1H,dd, J=2, 2 Hz), 8.55 (1H, d, J=2 Hz), 8.80 (1H, d, J=2 Hz).

EXAMPLE 570 ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz),1.41-1.54 (4H, m), 2.19 (2H, t, J=7 Hz), 2.50-2.61 (2H, m), 2.66 (4H, t,J=4 Hz), 2.85 (4H, t, J=4 Hz), 3.01 (2H, q, J=7 Hz), 3.67 (2H, s), 4.10(2H, q, J=7H), 5.88 (H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.88 (1H, dd,J=2, 2 Hz), 8.55 (1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz).

EXAMPLE 571 ethyl5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

¹H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz),1.40-1.55 (4H, m), 2.18 (2H, t, J=7 Hz), 2.48-2.66 (12H, m), 3.02 (2H,q, J=7 Hz), 3.61 (2H, t, J=5 Hz), 3.66 (2H, s), 4.10 (2H, q, J=7 Hz),5.88 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.88 (1H, dd, J=2, 2 Hz),8.55 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

EXAMPLE 572 ethyl4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (300 MHz, CDCl₃) δ 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz),1.70 (2H, t, J=7, 7 Hz), 2.19 (2H, t, J=7 Hz), 2.50-2.67 (6H, m), 2.86(4H, t, J=5 Hz), 3.02 (2H, q, J=7 Hz), 3.70 (2H, s), 4.05 (2H, q, J=5Hz), 5.89 (1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.74 (1H, dd, J=2, 2Hz), 8.52 (1H, d, J=2 Hz), 8.68 (1H, d, J=2 Hz).

EXAMPLE 573 ethyl4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (300 MHz, CDCl₃) δ 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz),1.72 (2H, tt, J=7, 7 Hz), 2.20 (2H, t, J=7 Hz), 2.56-2.69 (6H, m), 3.02(2H, q, J=7 Hz), 3.68-3.71 (6H, m), 4.05 (2H, q, J=7 Hz) 5.89 (1H, d,J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.74 (1H, dd, J=2, 2 Hz), 8.53 (1H, d,J=2 Hz), 8.69 (1H, d, J=2 Hz).

EXAMPLE 574 ethyl3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (300 MHz, CDCl₃) δ 1.21 (3H, t, J=7 Hz), 1.34 (3H, t, J=7 Hz),2.47-2.54 (2H, m), 2.59 (4H, t, J=5 Hz), 2.81-2.95 (2H, m), 3.02 (2H, q,J=7 Hz), 3.67 (4H, t, J=5 Hz), 3.69 (2H, s), 4.07 (2H, q, J=7 Hz), 5.90(1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.88 (1H, dd, J=2, 2 Hz), 8.55(1H, d, J=2 Hz), 8.79 (1H, d, J=2 Hz).

EXAMPLE 575 ethyl4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (300 MHz, CDCl₃) δ 1.21 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz),1.73 (2H, tt, J=7, 7 Hz), 2.20 (2H, t, J=7 Hz), 2.55-2.69 (6H, m), 3.02(2H, q, J=7 Hz), 3.69 (4H, t, J=5 Hz), 4.05 (2H, q, J=7 Hz), 5.89 (1H,d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.89 (1H, dd, J=2, 2 Hz), 8.57 (1H, d,J=2 Hz), 8.79 (1H, d, J=2 Hz).

EXAMPLE 576 ethyl4-{4-(5-chloro-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H NMR (300 MHz, CDCl₃) δ 0.46-0.52 (4H, m), 1.21 (3H, t, J=7 Hz), 1.38(3H, t, J=7 Hz), 1.71 (2H, tt, J=8, 8 Hz), 2.21 (2H, t, J=8 Hz),2.32-2.39 (1H, m), 2.45-2.54 (2H, m), 3.04 (2H, q, J=7 Hz), 4.06 (2H, q,J=7 Hz), 4.07 (2H, s), 5.89 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 7.72(1H, dd, J=2, 2 Hz), 8.50 (1H, d, J=2 Hz), 8.68 (1H, d, J=2 Hz).

EXAMPLE 577 ethyl5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-phenoxyethyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

¹H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz),1.40-1.56 (4H, m), 2.18 (2H, t, J=8 Hz), 2.41-2.52 (2H, m), 3.04 (2H, q,J=7 Hz), 3.19 (2H, t, J=5 Hz), 4.07 (2H, s), 4.09 (2H, q, J=7 Hz), 4.17(2H, t, J=5 Hz), 5.90 (1H, d, J=4 Hz), 6.57 (1H, d, J=4 Hz), 6.92-6.98(3H, m), 7.29-7.32 (2H, m), 7.86 (1H, dd, J=2, 2 Hz), 8.54 (1H, d, J=2Hz), 8.78 (1H, d, J=2 Hz).

EXAMPLE 578 ethyl5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-hydroxyethyl)(methyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

¹H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz),1.42-1.63 (4H, m), 2.20 (2H, t, J=8 Hz), 2.38 (3H, s), 2.53-2.64 (2H,m), 2.75 (2H, t, J=5 Hz), 3.02 (2H, q, J=7 Hz), 3.66 (2H, t, J=5 Hz),3.77 (2H, s), 4.10 (2H, q, J=7 Hz), 5.90 (1H, d, J=4 Hz), 6.59 (1H, d,J=4 Hz), 7.88 (1H, dd, J=2, 2 Hz), 8.55 (1H, d, J=2 Hz), 8.78 (1H, d,J=2 Hz).

EXAMPLE 579 ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-piperidinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

15 ¹H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz),1.42-1.58 (6H, m), 1.69 (4H, tt, J=5, 5 Hz), 2.18 (2H, t, J=8 Hz),2.53-2.64 (2H, m), 3.02 (2H, q, J=7 Hz), 3.19 (4H, t, J=5 Hz), 3.60 (2H,s), 4.07 (2H, q, J=7 Hz), 5.86 (1H, d, J=5 Hz), 6.54 (1H, d, J=5 Hz),7.89 (1H, dd, J=2, 2 Hz), 8.56 (1H, d, J=2 Hz), 8.75 (1H, d, J=2 Hz).

EXAMPLE 580 ethyl3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4-thiomorpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz),2.46 (2H, t, J=8 Hz), 2.64 (4H, t, J=5 Hz), 2.86 (6H, m), 3.02 (2H, q,J=7 Hz), 3.69 (2H, s), 4.06 (2H, q, J=7 Hz), 5.91 (1H, d, J=5 Hz), 6.60(1H, d, J=5 Hz), 7.88 (1H, dd, J=2, 2 Hz), 856(1H, d, J=2 Hz), 8.80(1H,d, J=2 Hz).

EXAMPLE 581 ethyl3-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}pyrrolo[1,2-b]pyridazin-3-yl)propanoate

¹H NMR (300 MHz, CDCl₃) δ 1.21 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz),2.46-2.63 (12H, m), 2.80-2.94 (2H, m), 3.03 (2H, q, J=7 Hz), 3.61 (2H,t, J=5 Hz), 3.70 (2H, s), 4.08 (2H, q, J=7 Hz), 5.90 (1H, d, J=5 Hz),6.59 (1H, d, J=5 Hz), 7.88 (1H, dd, J=2, 2 Hz), 8.56 (1H, d, J=2 Hz),8.79 (1H, d, J=2 Hz).

EXAMPLE 582 ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(1-pyrrolidinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz),1.40-1.55 (4H, m), 1.75-1.80 (4H, m), 2.19 (2H, t, J=7 Hz), 2.54-2.66(6H, m), 3.02 (2H, q, J=7 Hz), 3.76-3.81 (2H, m), 4.10 (2H, q, J=7 Hz),5.87 (1H, d, J=5 Hz), 6.55 (1H, d, J=5 Hz), 7.89 (1H, dd, J=2, 2 Hz),8.56 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz).

EXAMPLE 583 ethyl5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(4-phenyl-1-piperazinyl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (300 MHz, CDCl₃) δ 1.21 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz),1.41-1.54 (4H, m), 2.17 (2H, t, J=7 Hz), 2.53-2.68 (2H, m), 2.75 (4H, t,J=5 Hz), 3.03 (2H, q, J=7 Hz), 3.19 (4H, t, J=5 Hz), 3.73 (2H, s), 4.07(2H, q, J=7 Hz), 5.89 (1H, d, J=5 Hz), 6.58 (H, d, J=5 Hz), 6.85 (1H,dd, J=8, 8 Hz), 6.93 (2H, J=2.08 Hz), 7.25 (2H, J=8 Hz), 7.89 (1H, dd,J=2, 2 Hz), 8.56 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

EXAMPLE 584 ethyl5-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[(2-methoxyethyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

¹H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz),1.41-1.60 (4H, m), 2.19 (2H, t, J=7 Hz), 2.43-2.52 (2H, m), 2.96 (2H, t,J=5 Hz), 3.03 (2H, q, J=7 Hz), 3.40 (3H, s), 3.58 (2H, t, J=5 Hz), 3.99(2H, s), 4.10 (2H, q, J=7 Hz), 5.89 (1H, d, J=5 Hz), 6.56 (1H, d, J=5Hz), 7.87 (1H, dd, J=2, 2 Hz), 8.54 (1H, d, J=2 Hz), 8.78 (1H, d, J=2Hz).

The following compound(s) was (were) obtained in a similar manner tothat of Example 385.

EXAMPLE 5853-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]-N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]propanamide

¹H-NMR (CDCl₃) δ 1.37 (3H, 1, J=7 Hz), 2.25-3.10 (6H, m), 3.49 (3H, s),3.58 (4H, m), 3.81 (2H, m), 4.55 (2H, s), 5.97 (1H, d, J=5 Hz), 6.54(1H, s), 6.64 (1H, d, J=5 Hz), 7.93 (1H, m), 8.52 (1H, m), 8.78 (1H, m).

EXAMPLE 586 tert-butyl[2-({3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoyl}amino)ethyl]carbamate

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.43 (9H, s), 2.26 (2H, m), 2.88(2H, m), 3.04 (2H, q, J=7 Hz), 3.20 (2H, m), 3.28 (2H, m), 3.48 (3H, s),4.67 (2H, s), 4.85 (1H, s, br), 5.93 (1H, d, J=5 Hz), 6.20 (1H, s, br),6.63 (1H, d, J=5 Hz), 7.88 (1H, m), 8.53 (1H, m), 8.79 (1H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 330.

EXAMPLE 587 ethyl5-[2-{[2-(benzylamino)-2-oxoethoxy]methyl}-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.34 (3H, t, J=7 Hz), 1.33-1.55(4H, m), 2.12 (2H, t, J=7 Hz), 2.43 (3H, s), 2.40-2.56 (2H, m), 2.96(2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 4.19 (2H, s), 4.52 (2H, d, J=7Hz), 4.76 (2H, s), 5.93 (1H, d, J=4 Hz), 6.59 (1H, d, J=4 Hz), 7.06 (1H,br), 7.23-7.38 (5H, m), 7.49 (1H, s), 8.40 (1H, s), 8.54 (1H, s).

MS (ESI⁺): m/z 543.

The following compound(s) was (were) obtained in a similar manner tothat of Example 333.

EXAMPLE 588 ethyl4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(4H-1,2,4-triazol-4-ylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H-NMR (CDCl₃) δ 1.22-1.34 (6H, m), 1.67 (2H, m), 2.23 (2H, m), 2.51(2H, m), 2.98 (2H, q, J=7 Hz), 4.21 (2H, q, J=7 Hz), 5.67 (2H, m), 5.97(1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 7.85 (1H, m), 7.96 (1H, s), 8.34(1H, s), 8.53 (1H, m), 8.79 (1H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 336.

EXAMPLE 589 ethyl5-(7-ethyl-4-(5-methyl-3-pyridinyl)-2-{[(phenylsulfonyl)amino]methyl}pyrrolo[1,2-b]pyridazin-3-yl)pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.26-1.57(4H, m), 2.16 (2H, t, J=7 Hz), 2.33-2.46 (2H, m), 2.42 (3H, s), 2.98(2H, q, J=7 Hz), 4.11 (2H, q, J=7 Hz), 4.38 (2H, m), 5.91 (1H, br), 5.92(1H, d, J=4 Hz), 6.58 (1H, d, J=4 Hz), 7.43-7.55 (4H, m), 7.93 (2H, d,J=8 Hz), 8.33 (1H, d, J=2 Hz), 8.54 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 535.

The following compound(s) was (were) obtained in a similar manner tothat of Example 340.

EXAMPLE 590 ethyl4-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylamino)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H-NMR (CDCl₃) δ 0.48 (4H, m), 1.19 (3H, t, J=7 Hz), 1.37 (3H, t, J=7Hz), 1.70 (2H, t, J=7 Hz), 2.22 (2H, m), 2.50 (2H, m), 2.95-3.07 (3H,m), 3.96-4.12 (4H, m), 5.90 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.88(1H, m), 8.54 (1H, m), 8.77(1H, m).

EXAMPLE 591

To a suspension of LiAlH4 (113 mg) in THF (10 mL) was addedethyl[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate(600 mg) under ice-water cooling and the mixture was stirred at 0° C.for 2 hours. To the mixture was added potassium sodium tartrate solutionand the insolubles were filterred off. After evaporation of solvent, theresidue was partitioned between AcOEt and water. The organic layer wasseparated, washed with brine, dried over MgSO₄, and evaporated in vacuo.The residue was purified by silica gel column chromatography elutingwith a mixture of hexane and AcOEt (5:1-1:1) to give2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethanolas yellow oil (246 mg).

2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethanol

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 2.60 (3H, s), 2.72-2.84 (2H, m),3.03 (2H, q, J=7 Hz), 3.65 (2H, t, J=7 Hz), 5.89 (1H, d, J=4 Hz), 6.55(1H, d, J=4 Hz), 7.91 (1H, t, J=2 Hz), 8.56 (1H, d, J=2 Hz), 8.76 (1H,d, J=2 Hz).

MS (ESI⁺): m/z 360 362.

EXAMPLE 592

A mixture of3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]propanoicacid (1.07 g), diphenylphosphoryl azide (1.14 g) and Et3N (0.576 mL) inBuOH (30 mL) was heated under reflux for 2 hours. After evaporation ofsolvent, the residue was partitioned between AcOEt and water. Theorganic layer was separated, washed with aq NaHCO₃ solution and brine,dried over MgSO₄, and evaporated in vacuo. The residue was purified bysilica gel column chromatography eluting with a mixture of hexane andAcOEt (20:1-3:1) to give tert-butyl{2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethyl}carbamateas yellow oil (450 mg).

tert-butyl{2-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]ethyl}carbamate

¹H NMR (CDCl₃) δ 1.37 (9H, s), 1.37 (3H, t, J=7 Hz), 2.64 (3H, s),2.62-2.75 (2H, m), 3.03 (2H, q, J=7 Hz), 3.10-3.27 (2H, m), 4.40-4.52(1H, m), 5.89 (1H, d, J=4 Hz), 6.55 (1H, d, J=4 Hz), 7.89 (1H, m), 8.53(1H, m), 8.77 (1H, m).

EXAMPLE 593

To a suspension of 60% NaH (74 mg) in DMF (3 mL) was added ethyl3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate(200 mg) under ice-water cooling, and the mixture was stirred at 0° C.for 0.5 hour. To this was added 3-(bromomethyl)pyridine hydrobromide(234 mg) under ice-water cooling, and the mixture was stirred at ambienttemperature for 2 hours. The mixture was partitioned between AcOEt andwater. The aqueous layer was separated, acidified to pH 3-4 with HCl andextracted with AcOEt. The organic layer was washed with water and brine,dried over MgSO₄, and evaporated in vacuo. The residue was purified bysilica gel column chromatography eluting with a mixture of CHCl₃ andMeOH (100:1-20:1) to give3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid as a yellow powder (110 mg).

3-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=7 Hz), 2.41 (2H, t, J=7 Hz), 2.80-2.98(2H, m), 3.04 (2H, q, J=7 Hz), 4.70 (2H, s), 4.83 (2H, s), 5.93 (1H, d,J=4 Hz), 6.63 (1H, d, J=4 Hz), 7.32-7.38 (1H, m), 7.81 (1H, d, J=8 Hz),7.87 (1H, m), 8.52 (1H, d, J=8 Hz), 8.53 (1H, d, J=2 Hz), 8.63 (1H, s),8.77 (1H, d, J=2 Hz).

The following compound(s) was (were) obtained in a similar manner tothat of Example 593.

EXAMPLE 5944-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-methoxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.72-1.83 (2H, m), 2.28 (2H, t,J=7 Hz), 2.60-2.77 (2H, m), 3.03 (2H, q, J=7 Hz), 3.39 (3H, s), 3.62(2H, m), 3.77 (2H, m), 4.75 (2H, s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d,J=4 Hz), 7.92 (1H, m), 8.56 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 474 476, MS (ESI⁺): m/z 476 478.

EXAMPLE 5953-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.48-2.62 (2H, m), 2.98-3.10 (2H,m), 3.05 (2H, q, J=7 Hz), 4.82 (2H, s), 4.88 (2H, s), 5.94 (1H, d, J=4Hz), 6.63 (1H, d, J=4 Hz), 7.27 (1H, m), 7.48 (1H, d, J=8 Hz), 7.77 (1H,t, J=8 Hz), 7.90 (1H, m), 8.56 (2H, m), 8.80 (1H, m).

MS (ESI⁺): m/z 495 497.

EXAMPLE 5963-{4-(5-bromo-3-pyridinyl)-2-[(cyclopropylmethoxy)methyl]-7-ethylpyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (CDCl₃) δ 0.25 (2H, m), 0.58 (2H, m), 1.12 (1H, m), 1.37 (3H, t,J=7 Hz), 2.40-2.63 (2H, m), 2.85-3.05 (2H, m), 3.02 (2H, q, J=7 Hz),3.42 (2H, d, J=7 Hz), 4.73 (2H, s), 5.93 (1H, d, J=4 Hz), 6.63 (1H, d,J=4 Hz), 7.89 (1H, m), 8.55 (1H, d, J=2 Hz), 8.77 (1H, d, J=2 Hz).

MS (ESI⁻): m/z 456 458, MS (ESI⁺): m/z 458 460.

EXAMPLE 5973-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.48 (2H, t, J=7 Hz), 2.85-3.09(2H, m), 3.06 (2H, q, J=7 Hz), 4.84 (2H, s), 4.92 (2H, s), 5.96 (1H, d,J=4 Hz), 6.65 (1H, d, J=4 Hz), 7.90 (1H, m), 8.48-8.62 (3H, m), 8.77(2H, m).

EXAMPLE 598

A mixture of ethyl4-(4-(5-bromo-3-pyridinyl)-7-ethyl-2-{[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]methyl}pyrrolo[1,2-b]pyridazin-3-yl)butanoate(89 mg) and pyridinium p-toluenesulfonate (0.8 mg) in MeOH (5 mL) washeated under reflux for 2 hours. After evaporation of solvent, theresidue was purified by silica gel column chromatography eluting with amixture of hexane and AcOEt (10:1-1:1) to give ethyl4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-hydroxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoateas yellow oil (69 mg).

ethyl4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-hydroxyethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H NMR (CDCl₃) δ 1.22 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.69-1.84(2H, m), 2.22 (2H, t, J=7 Hz), 2.53-2.72 (2H, m), 3.03 (2H, q, J=7 Hz),3.76 (2H, m), 3.83 (2H, m), 4.07 (2H, q, J=7 Hz), 4.79 (2H, s), 5.93(1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.89 (1H, m), 8.56 (1H, d, J=2Hz), 8.79 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 490 492.

EXAMPLE 599

To a suspension of 60% NaH (695 mg) in DMF (3 mL) was added ethyl5-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate5 (200 mg) under ice-water cooling and the mixture was stirred at 0° C.for 0.5 hour. To this was added 4-morpholinecarbonyl chloride (659 mg)and the mixture was stirred at ambient temperature for 15 hours. Themixture was partitioned between AcOEt and water. The organic layer wasseparated, washed with water and brine, dried over MgSO₄, and evaporatedin vacuo. The residue was purified by silica gel column chromatographyeluting with a mixture of hexane and AcOEt (20:1-1:1) to give[4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methyl4-morpholinecarboxylate as yellow oil (75 mg).

[4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methyl4-morpholinecarboxylate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.40-1.60(4H, m), 2.18 (2H, t, J=7 Hz), 2.42-2.54 (2H, m), 3.03 (2H, q, J=7 Hz),3.53-3.57 (4H, m), 3.63-3.78 (4H, m), 4.09 (2H, q, J=7 Hz), 5.33 (2H,s), 5.93 (1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.87 (1H, m), 8.54 (1H,d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 573 575.

The following compound(s) was (were) obtained in a similar manner tothat of Example 599.

EXAMPLE 600 ethyl5-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.35-1.60(4H, m), 2.17 (2H, t, J=7 Hz), 2.44-2.57 (2H, m), 2.98 (6H, s), 3.03(2H, q, J=7 Hz), 4.09 (2H, q, J=7 Hz), 5.30 (2H, s), 5.93 (1H, d, J=4Hz), 6.61 (1H, d, J=4 Hz), 7.87 (1H, m), 8.54 (1H, d, J=2 Hz), 8.78 (1H,d, J=2 Hz).

MS (ESI⁺): m/z 531 533.

EXAMPLE 601[4-(5-bromo-3-pyridinyl)-3-(5-ethoxy-5-oxopentyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methyl1-pyrrolidinecarboxylate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.38-1.60(4H, m), 1.86-1.98 (4H, m), 2.17 (2H, t, J=7 Hz), 2.44-2.57 (2H, m),3.03 (2H, q, J=7 Hz), 3.36-3.52 (4H, m), 4.11 (2H, q, J=7 Hz), 5.32 (2H,s), 5.92 (1H, d, J=4 Hz), 6.61 (1H, d, J=4 Hz), 7.87 (1H, m), 8.55 (1H,d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

EXAMPLE 602 ethyl5-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[({[methyl(phenyl)amino]carbonyl}oxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.32-1.57(4H, m), 2.13 (2H, t, J=7 Hz), 2.33-2.48 (2H, m), 3.03 (2H, q, J=7 Hz),3.38 (3H, s), 4.08 (2H, q, J=7 Hz), 5.34 (2H, s), 5.92 (1H, d, J=4 Hz),6.60 (1H, d, J=4 Hz), 7.20-7.38 (5H, m), 7.83 (1H, s), 8.49 (1H, s),8.77 (1H, s).

EXAMPLE 603[4-(5-bromo-3-pyridinyl)-3-(4-ethoxy-4-oxobutyl)-7-ethylpyrrolo[1,2-b]pyridazin-2-yl]methyl4-morpholinecarboxylate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.37 (3H, t, J=7 Hz), 1.63-1.80(2H, m), 2.22 (2H, t, J=7 Hz), 2.44-2.65 (2H, m), 3.03 (2H, q, J=7 Hz),3.54 (4H, m), 3.68 (4H, m), 4.05 (2H, q, J=7 Hz), δ 37 (2H, s), 5.94(1H, d, J=4 Hz), 6.62 (1H, d, J=4 Hz), 7.87 (1H, m), 8.55 (1H, d, J=2Hz), 8.78 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 559 561.

EXAMPLE 604 ethyl4-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 1.66-1.79(2H, m), 2.20 (2H, t, J=7 Hz), 2.46-2.62 (2H, m), 2.97 (6H, s), 3.03(2H, q, J=7 Hz), 4.04 (2H, q, J=7 Hz), 5.34 (2H, s), 5.93 (1H, d, J=4Hz), 6.63 (1H, d, J=4 Hz), 7.89 (1H, m), 8.56 (1H, d, J=2 Hz), 8.78 (1H,d, J=2 Hz).

MS (ESI⁺): m/z 517 519.

EXAMPLE 605 ethyl3-[4-(5-bromo-3-pyridinyl)-2-({[(dimethylamino)carbonyl]oxy}methyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H NMR (CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.36 (3H, t, J=7 Hz), 2.37 (2H,t, J=7 Hz), 2.82-2.93 (2H, m), 2.97 (6H, s), 3.03 (2H, q, J=7 Hz), 4.05(2H, q, J=7 Hz), 5.32 (2H, s), 5.96 (1H, d, J=4 Hz), 6.63 (1H, d, J=4Hz), 7.88 (1H, m), 8.54 (1H, d, J=2 Hz), 8.78 (1H, d, J=2 Hz).

EXAMPLE 606

To a solution of sodium hydride (93.1 mg) in DMF (4 mL) was added ethyl3-[4-(3-chlorophenyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate(150 mg) under ice water cooling and the mixture was stirred at thistemperature for 1 hour. To this was added 4-(bromomethyl)pyridinehydrobromide (196 mg) and the mixture was stirred for 1 hour at ambienttemperature. The reaction was quenched by adding water. The mixture wasextracted with CHCl₃. The organic layer was washed with water and brine,dried over MgSO₄ and evaporated in vacuo. The residue was purified bysilica gel column chromatography eluting with a mixture ofCHCl₃-MeOH=30-1 to give3-{4-(3-chlorophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid (18 mg) as a yellow solid.

3-{4-(3-chlorophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.39 (3H, t, J=7 Hz), 2.33 (2H, t, J=7 Hz),2.84-2.91 (2H, m), 3.04 (2H, q, J=7 Hz), 4.73 (2H, s), 4.82 (2H, s),5.96 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz), 7.23-7.26 (1H, m), 7.36-7.38(3H, m), 7.42-7.44 (2H, m), 8.41 (2H, d, J=5 Hz).

MS (m/z) 450 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Example 606.

EXAMPLE 6073-{4-(3-chlorophenyl)-7-ethyl-2-[(3-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.39 (3H, t, J=7 Hz), 2.32-2.38 (2H, m),2.84-2.92 (2H, m), 3.04 (2H, q, J=7 Hz), 4.70 (2H, s), 4.82 (2H, s),5.94 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.21-7.24 (1H, m), 7.31-7.36(2H, m), 7.40-7.42 (2H, m), 7.80 (2H, d, J=8 Hz), 8.51 (1H, d, J=5 Hz),8.64 (1H, s).

EXAMPLE 6083-{4-(3-chlorophenyl)-7-ethyl-2-[(2-pyrazinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}propanoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.42 (2H, t, J=7 Hz),2.91-2.97 (2H, m), 3.03 (2H, q, J=7 Hz), 4.83 (2H, s), 4.90 (2H, s),5.96 (2H, d, J=5 Hz), 6.62 (2H, d, J=5 Hz), 7.23-7.26 (1H, m), 7.36 (1H,s), 7.43-7.44 (2H, m), 8.51-8.53 (2H, m), 8.75 (1H, s).

EXAMPLE 609

A solution of5-[7-ethyl-2-methyl-4-(2-vinyl-4-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid (15 mg) in MeOH was added 10% Pd/C (2 mg). The mixture was stirredunder under hydrogen atomosphere (1 atm) for 6 h. The reaction mixturewas filtered through Celite and the filtrate was concentrarted in vacuo.The residue was triturated with hexane to give5-[7-ethyl-4-(2-ethyl-4-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid (14 mg) as an yellow solid.

5-[7-ethyl-4-(2-ethyl-4-pyridinyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 1.29-1.64 (10H, m), 2.18-2.30 (2H, m), 2.45-2.48 (2H,m), 2.56 (3H, s), 2.91-3.06 (4H, m), 5.84 (1H, d, J=5 Hz), 6.53 (1H, d,J=16 Hz), 6.51 (1H, d, J=5 Hz), 7.25-7.32 (2H, m), 8.69 (1H, br s).

EXAMPLE 610

To a solution of ethyl4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(hydroxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate(70.0 mg) in toluene (1 mL) was added tributylphosphine (0.098 mL),1,3-oxazolidin-2-one (34.1 mg) in that order in an ice bath. Afterstirring for 5 minutes, to the mixture was added1,1′-(azodicarbonyl)dipiperidine (98.9 mg). The mixture was stirred for10 minutes in the bath, and 8 hours at room temperature. Hexane (5 mL)was added, and the mixture was filtered. The filtrate was evaporated.Preparative thin layer chromatography (ethyl acetate-hexane=1-1)afforded ethyl4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoateas an yellow gum (25.0 mg).

ethyl4-{4-(5-bromo-3-pyridinyl)-7-ethyl-2-[(2-oxo-1,3-oxazolidin-3-yl)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoate

¹H-NMR (CDCl₃) δ 1.20 (3H, t, J=7 Hz), 1.369 (3H, t, J=7 Hz), 1.65 (3H,t, J=7 Hz), 2.25 (2H, t, J=7 Hz), 2.51 (2H, m), 2.99 (2H, q, J=7 Hz),3.79 (2H, t, J=7 Hz), 4.04 (2H, q, J=7 Hz), 4.43 (2H, t, J=7 Hz), 4.69(2H, m), 5.95 (1H, d, J=5 Hz), 6.61 (1H, d, J=5 Hz), 7.87 (1H, m), 8.55(1H, m), 8.80 (1H, m).

EXAMPLE 611

To a solution of2-bromo-4-[3-(ethoxycarbonyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzoicacid (50.0 mg) in tetrahydrofuran (1 mL) was added a solution of 1 Mborane-tetrahydrofuran complex (0.348 mL) in an ice bath. After stirringfor 2 hours at room temperature, additional solution of theborane-tetrahydrofuran complex (0.348 mL) was added. The mixture wasstirred for 15 hours at room temperature. The mixture was parititionedbetween ethyl acetate and 1 N hydrochloric acid. The organic layer waswashed with water, saturated sodium bicarbonate, and brine, dried overmagnesium sulfate, and evaporated to give ethyl4-[3-bromo-4-(hydroxymethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylateas an yellow oil (54.2 mg).

ethyl4-[3-bromo-4-(hydroxymethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate

¹H-NMR (CDCl₃) δ 0.99 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.59 (3H,s), 3.03 (2H, q, J=7 Hz), 4.07 (2H, q, J=7 Hz), 4.82 (2H, s), 6.33 (1H,d, J=5 Hz), 6.66 (1H, d, J=5 Hz), 7.44 (1H, d, J=8 Hz), 7.58 (1H, d, J=8Hz), 7.67 (1H, s).

EXAMPLE 612

To a solution of2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}ethoxy)ethylacetate (62.0 mg) in methanol (1 mL) was added potassium carbonate (22.2mg). After stirring for 1.5 hour, The solvent was evaporated off.Preparative thin layer chromatography (CHCl₃-MeOH=20-1) affroded thedesired product as an yellow gum (54.1 mg). The gum was dissolved in 1 NHCl (1 mL), and the solution was lyophilized to give a dark green gum,which was crystalyzed upon standing. The crystal was triturated indiisopropyl ether to give2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}ethoxy)ethanolhydrochloride as an yellow powder (403 mg).

2-(2-{2-[7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]ethoxy}ethoxy)ethanolhydrochloride

¹H-NMR (DMSO-d₆): 1.29 (3H, t, J=7 Hz), 2.51 (3H, s), 2.56 (3H, s), 2.62(2H, m), 2.94 (2H, q, J=7 Hz), 3.30-3.47 (10H, m), 5.84 (1H, d, J=5 Hz),6.59 (1H, d, J=5 Hz), 8.26 (1H, m), 8.77 (1H, m), 8.85 (1H, m).

EXAMPLE 613

A mixture of ethyl5-[2-(bromomethyl)-4-(3-cyanophenyl)-7-ethylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate(70.0 mg), phenol (21.1 mg), and pottassium carbonate (31.0 mg) inN,N-dimethylformamide was stirred for 25 hours at room temperature. Themixture was partitioned between ethyl acetate and 1 N hydrochloric acid.The organic layer was washed with water, saturated sodium bicarbonate,and brine, dried over magnesium sulfate, and evaporated to give ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-(phenoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoateas an yellow gum (775 mg, 108%).

ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-(phenoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H-NMR (CDCl₃) δ 1.21 (3H, t, J=7 Hz), 1.35-1.53 (7H, m), 2.07 (2H, m),2.54 (2H, m), 3.03 (2H, q, J=7 Hz), 4.05 (2H, q, J=7 Hz), 5.24 (2H, s),5.86 (1H, d, J=5 Hz), 6.65 (1H, d, J=5 Hz), 6.80-7.01 (3H, m), 7.03 (2H,d, J=9 Hz), 7.32 (2H, t, J=9 Hz), 7.55-7.63 (2H, m), 7.67 (1H, s), 7.76(1H, m).

MS (ESI⁺): m/z 482 (M+H)

EXAMPLE 614

A mixture of4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yltrifluoromethanesulfonate (50.0 mg), 3-furylboronic acid (23.6 mg),dichlorobis(triphenylphosphine)palladium (3.71 mg), and 2 N sodiumcarbonate (44.8 mg in 0.2 mL of water) in dioxane was stirred for 20minutes at 85° C. The mixture was partitioned between EtOAc and water,and the organic layer was washed with brine, dried, and evaporated.Preparative thin layer chromatography (EtOAc-hexane=1-1) afforded3-[7-ethyl-2-(2-furyl)-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrileas an orange solid (11.5 mg).

3-[7-ethyl-2-(2-furyl)-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

¹H-NMR (CDCl₃) δ 1.40 (3H, t, J=7 Hz), 3.10 (2H, q, J=7 Hz), 3.20 (3H,s), 6.30 (1H, d, J=5 Hz), 6.63 (1H, m), 6.87 (1H, d, J=5 Hz), 6.95 (1H,m), 7.60-7.73 (4H, m), 8.79 (1H, m).

EXAMPLE 615

To a solution of5-[4-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid (100 mg) in tetrahydrofurane (1 mL) was added 1 Mborane-tetrahydrofurane comples (0.708 mL) in an ice bath under anitrogen atmosphere. The mixture was stirred for 4 hours in the bath and1 hour at room temperature. The reaction was quenched by adding 1 Nhydrochloric acid (1 mL). The mixture was partitioned between EtOAc (10mL) and 1 N hydrochloric acid (5 mL). The organic layer was washed withwater and brine, dried over magnesium sulfate, and evaporated.Preparative thin layer chromatography eluting with acetone-hexane=1-2afforded3-[7-ethyl-3-(5-hydroxypentyl)-2-phenylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrileas an yellow gum (104 mg).

3-[7-ethyl-3-(5-hydroxypentyl)-2-phenylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile

¹H-NMR (CDCl₃) δ 0.98-1.17 (6H, m), 1.36 (3H, t, J=7 Hz), 2.38 (2H, m),2.58 (2H, m), 3.34 (2H, m), 5.89 (1H, d, J=5 Hz), 6.62 (1H, d, J=5 Hz),7.45-7.53 (5H, m), 7.55-7.67 (4H, m).

MS (ESI⁺): m/z 410 (M+H)

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 24.

Preparation 343

ethyl 2-[(5-bromo-3-pyridinyl)carbonyl]-4-methoxy-3-oxobutanoate

¹H NMR (CDCl₃) δ 0.96-1.10 (3H, m), 3.23 (1.5H, s), 3.49 (1.5H, s),4.00-4.34 (4H, m), 4.57 (1H, s), 8.00 (0.15H, br s), 8.23 (0.15H, br s),8.60-8.91 (2H, m).

Preparation 344

1-tert-butyl 8-ethyl2-acetyl-2-[(6-cyano-3-pyridinyl)carbonyl]octanedioate

¹H NMR (CDCl₃) δ 1.22-1.46 (16H, m), 1.55-1.70 (2H, m), 2.17-2.34 (4H,m), 2.48 (3H, s), 4.14 (2H, q, J=8 Hz), 7.77 (1H, br d, J=8 Hz), 8.17(1H, dd, J=8, 2 Hz), 8.97 (1H, d, J=2 Hz).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 78.

Preparation 345

ethyl 7-[(6-cyano-3-pyridinyl)carbonyl]-8-oxononanoate

¹H NMR (CDCl₃) δ 1.20-1.45 (7H, m), 1.52-1.70 (2H, m), 1.92-2.14 (2H,m), 2.17-2.39 (5H, m), 4.11 (2H, q, J=8 Hz), 4.40 (1H, t, J=8 Hz), 7.84(1H, br d, J=8 Hz), 8.39 (1H, m), 9.23 (1H, br s).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 130.

Preparation 346

ethyl 4-methoxy-3-oxobutanoate

¹H NMR (CDCl₃) δ 1.28 (3H, t, J=8 Hz), 3.42 (3H, s), 3.51 (2H, s), 4.09(2H, s), 4.20 (2H, q, J=8 Hz).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 338.

Preparation 347

benzyl 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-5-bromobenzoate

¹H-NMR (CDCl₃) δ 1.28 (3H, t, J=7 Hz), 2.75 (2H, q, J=7 Hz), 5.37 (2H,s), 5.73 (2H, s), 5.94 (1H, d, J=5 Hz), 6.66 (1H, d, J=5 Hz), 7.35-7.48(5H, m), 7.99 (1H, s), 8.33 (1H, s), 8.38 (1H, s).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 321.

Preparation 348

benzyl 3-bromo-5-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate

¹H-NMR (CDCl₃) δ 1.29 (3H, t, J=7 Hz), 2.72 (2H, q, J=7 Hz), 5.37 (2H,s), 6.09 (1H, m), 6.78 (1H, m), 7.33-7.45 (5H, m), 8.15 (1H, s), 8.33(1H, s), 8.45 (1H, s).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 310.

Preparation 349

benzyl 3-bromo-5-(chlorocarbonyl)benzoate

Preparation 350

To a solution of benzyl 3-bromo-5-iodobenzoate (1.00 g) in THF (10 mL)was added 0.76 M isopropyl magnesium bromide (3.16 mL) in an ice bathunder a nitrogen atmosphere. After stirring for 0.5 hour, the mixturewas poured onto dryice. The mixture was warmed to room temperature over1 hour. The mixture was partitioned between EtOAc and 1 N HCl. Theorganic layer was washed with brine, dried over MgSO₄, and evaporated.Flash silica gel column chromatography (chloroform-methanol=50-0 to50-2) afforded 3-benzyloxycarbonyl-5-bromobenzoic acid as a white solid(273 mg).

3-[(benzyloxy)carbonyl]-5-bromobenzoic acid

¹H-NMR (DMSO-d₆) δ 5.39 (2H, s), 7.30-7.52 (5H, m), 8.29 (2H, s), 8.43(1H, s).

Preparation 351

A mixture of 3-bromo-5-iodobenzoic aicd (5.00 g) andN,N-dimethylformamide (0.059 mL) in dichloromethane (50 mL) was addedoxalyl chloride (1.47 mL) in an ice bath under a nitrogen atmosphere.After stirring for 1 hour, the volatile was evaporated off. The residuewas dissolved in dichloromethane (50 mL), and to the solution was addedbensyl alcohol (1.82 g) followe by triethyl amine (3.2 mL) in the icebath. The mixture was stirred for 2 hours at room temperature. Themixture was partitioned between EtOAc and water. The organic layer waswashed with water (two times), satd. NaHCO₃, and brine, dried over MgSO₄and evaporated. Flash silica gel column chromatography(EtOAc-hexanes=1/200 to 20/200) afforded benzyl 3-bromo-5-iodobenzoateas white crystals (5.95 g).

benzyl 3-bromo-5-iodobenzoate

¹H-NMR (CDCl₃) δ 5.35 (3H, s), 7.35-7.68 (5H, m), 8.04 (1H, s), 8.16(1H, m), 8.30 (1H, s).

The following compound(s) was (were) obtained in a similar manner tothat of Example 1.

EXAMPLE 615 benzyl3-bromo-5-[7-ethyl-2-methyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate

¹H-NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.88 (3H, s), 3.05 (3H, s), 3.06(2H, q, J=7 Hz), 5.35 (2H, s), 6.15 (1H, d, J=5 Hz), 6.72 (1H, d, J=5Hz), 7.33-7.45 (5H, m), 7.68 (1H, m), 7.94 (1H, m), 8.28 (1H, m).

EXAMPLE 6164-(3-cyanophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazine-3-carbonitrile

¹H NMR (CDCl₃) δ 1.42 (3H, t, J=8 Hz), 3.12 (2H, q, J=8 Hz), 6.60 (1H,d, J=5 Hz), 6.92 (1H, d, J=5 Hz), 7.50-7.58 (3H, m), 7.73 (1H, t, J=8Hz), 7.82-7.91 (3H, m), 7.93-8.01 (2H, m).

EXAMPLE 6172-tert-butyl-4-(3-chlorophenyl)-7-ethylpyrrolo[1,2-b]pyridazine-3-carbonitrile

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=8 Hz), 1.60 (9H, s), 3.05 (2H, q, J=8Hz), 6.48 (1H, d, J=5 Hz), 6.77 (1H, d, J=5 Hz), 7.45-7.54 (3H, m), 7.60(1H, br s).

The following compound(s) was (were) obtained in a similar manner tothat of reparation 78.

EXAMPLE 618 ethyl6-[4-(6-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoate

¹H NMR (CDCl₃) δ 1.15-1.64 (12H, m), 2.21 (1H, t, J=8 Hz), 2.32-2.44(2H, m), 2.56 (3H, s), 3.01 (2H, q, J=8 Hz), 4.10 (2H, q, J=8 Hz), 5.79(1H, d, J=5 Hz), 6.54 (1H, d, J=5 Hz), 7.85 (1H, br s), 8.30 (1H, br d,J=8 Hz), 8.72 (1H, br s).

MS (ESI⁺): m/z 405 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Example 21.

EXAMPLE 619 ethyl4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3-carboxylate

¹H NMR (CDCl₃) δ 1.04 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 3.06 (2H,q, J=8 Hz), 3.39 (3H, s), 4.10 (2H, q, J=8 Hz), 4.76 (2H, s), 6.33 (1H,d, J=5 Hz), 6.74 (1H, d, J=5 Hz), 7.96 (1H, br s), 8.61 (1H, br s), 8.78(1H, d, J=2 Hz).

MS (ESI⁺): m/z 418, 420 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Example 76.

EXAMPLE 6203-bromo-5-[7-ethyl-2-methyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoicacid

¹H-NMR (CDCl₃+CD3OD) δ 1.38 (3H, t, J=7 Hz), 2.86 (3H, s), 3.05 (3H, s),3.06 (2H, q, J=7 Hz), 6.19 (1H, d, J=5 Hz), 6.71 (1H, d, J=5 Hz), 7.53(1H, s), 7.90 (1H, s), 8.23 (1H, s).

EXAMPLE 621(2E)-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylicacid

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=8 Hz), 3.07 (2H, q, J=8 Hz), 3.51 (3H,s), 4.65 (2H, s), 5.96 (1H, d, J=15 Hz), 6.27 (1H, d, J=5 Hz), 6.74 (1H,d, J=5 Hz), 7.68 (1H, d, J=15 Hz), 7.93 (1H, m), 8.57 (1H, d, J=1 Hz),8.70 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 416, 418 (M+H).

EXAMPLE 6226-[4-(6-cyano-3-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]hexanoicacid

¹H NMR (CDCl₃) δ 1.15-1.69 (9H, m), 1.90-2.50 (4H, m), 2.56 (3H, s),3.01 (2H, q, J=8 Hz), 5.80 (1H, d, J=5 Hz), 6.51 (1H, d, J=5 Hz), 7.84(1H, dd, J=8, 2 Hz), 8.28 (1H, d, J=8 Hz), 8.51 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 377 (M+H).

EXAMPLE 622-26-{4-[6-(aminocarbonyl)-3-pyridinyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoicacid

¹H NMR (CDCl₃) δ 1.16-1.51 (9H, m), 2.10-2.24 (2H, m), 2.35-2.47 (2H,m), 2.58 (3H, s), 3.01 (2H, q, J=8 Hz), 5.85 (1H, d, J=5 Hz), 6.54 (1H,d, J=5 Hz), 7.22 (1H, br s), 7.90 (1H, dd, J=8, 1 Hz), 8.01 (1H, br s),8.34 (1H, d, J=8 Hz), 8.61 (1H, d, J=1 Hz).

MS (ESI⁺): m/z 395 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Example 147.

EXAMPLE 623 ethyl(2E)-3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylate

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=8 Hz), 1.39 (3H, t, J=8 Hz), 3.06 (2H,q, J=8 Hz), 3.51 (3H, s), 4.17 (2H, q, J=8 Hz), 4.64 (2H, s), 5.97 (1H,d, J=15 Hz), 6.24 (1H, d, J=5 Hz), 6.73 (1H, d, J=5 Hz), 7.51 (1H, d,J=15 Hz), 7.91 (1H, br s), 8.57 (1H, br s), 8.70 (1H, br s).

MS (ESI⁺): m/z 444, 446 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Example 200.

EXAMPLE 624[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=8 Hz), 3.05 (2H, q, J=8 Hz), 3.45-3.55(4H, m), 4.40 (2H, br d, J=7 Hz), 4.77 (2H, br s), 6.22 (1H, d, J=5 Hz),6.70 (1H, d, J=5 Hz), 8.11 (1H, m), 8.74 (1H, br s), 8.80 (1H, d, J=2Hz).

MS (ESI⁺): m/z 376, 378 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Example 205.

EXAMPLE 625(4E)-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]4-pentenoicacid

¹H NMR (CDCl₃) δ 1.37 (3H, t, J=8 Hz), 2.26-2.43 (4H, m), 2.50 (3H, s),3.01 (2H, q, J=8 Hz), 5.40 (1H, dt, J=15, 7 Hz), 6.05 (1H, d, J=5 Hz),6.20 (1H, d, J=15 Hz), 6.56 (1H, d, J=5 Hz), 7.28 (1H, br d, J=5 Hz),7.39 (1H, br s), 8.47 (1H, br d, J=5 Hz).

MS (ESI⁺): m/z 370 (M+H).

EXAMPLE 625-2(4Z)-5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-4-pentenoicacid

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=8 Hz), 1.87-2.00 (2H, m), 2.12 (2H, t,J=8 Hz), 2.42 (3H, s), 3.03 (2H, q, J=8 Hz), 5.58 (1H, dt, J=10, 8 Hz),6.17 (1H, d, J=5 Hz), 6.26 (1H, br d, J=10 Hz), 6.60 (1H, d, J=5 Hz),7.35 (1H, br d, J=5 Hz), 7.44 (1H, br s), 8.48 (1H, br d, J=5 Hz).

MS (ESI⁺): m/z 370 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Example 220.

EXAMPLE 6264-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3-carboxylicacid

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=8 Hz), 3.06 (2H, q, J=8 Hz), 3.44 (3H,s), 4.82 (2H, s), 6.36 (1H, d, J=5 Hz), 6.77 (1H, d, J=5 Hz), 8.09 (1H,br s), 8.65 (1H, br s), 8.72 (1H, br s).

MS (ESI⁺): m/z 390, 392 (M+H).

EXAMPLE 6274-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=8 Hz), 2.70 (3H, s), 3.06 (2H, q, J=8Hz), 6.26 (1H, d, J=5 Hz), 6.72 (1H, d, J=5 Hz), 7.32 (1H, dd, J=5, 1Hz), 7.43 (1H, br s), 8.50 (1H, d, J=5 Hz).

MS (ESI⁺): m/z 316 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Example 244.

EXAMPLE 6284-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carbaldehyde

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=8 Hz), 2.81 (3H, s), 3.09 (2H, q, J=8Hz), 6.43 (1H, d, J=5 Hz), 6.78 (1H, d, J=5 Hz), 7.34 (1H, br d, J=5Hz), 7.46 (1H, br s), 8.56 (1H, d, J=5 Hz), 9.76 (1H, s).

MS (ESI⁺): m/z 300 (M+H).

EXAMPLE 6294-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3-carbaldehyde

¹H NMR (CDCl₃) δ 1.41 (3H, t, J=8 Hz), 3.14 (2H, q, J=8 Hz), 3.55 (3H,s), 4.94 (2H, s), 6.50 (1H, d, J=5 Hz), 6.84 (1H, d, J=5 Hz), 7.95 (1H,br s), 8.12 (1H, br s), 8.84 (1H, br s), 9.85 (1H, s).

MS (ESI⁺): m/z 374, 376 (M+H).

EXAMPLE 630

A solution of phosphorus oxychloride (241 mg, 1.57 mmol) inN,N-dimethylformamide (4 mL) was stirred for 10 min at room temperature.The resulting mixture was cooled to 0° C., and a solution of ethyl4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate(428 mg, 1.31 mmol) in N,N-dimethylformamide (0.7 mL) was added. Theresulting mixture was warmed to 50° C., and stirred for 45 min. Sincethe starting material was remained, a solution of phosphorus oxychloride(621 mg, 0.67 mmol) in N,N-dimethylformamide (0.2 mL) was added, and themixture was stirred for 15 min. The resulting mixture was poured intoice-cooled water (10 mL), and extracted with ethyl acetate (30 mL). Theorganic layer was washed with water and saturated sodium bicarbonate.All the aqueous layer was extracted with ethyl acetate. The combinedorganic extract was washed with brine, dried over anhydrous magnesiumsulfate, and evaporated to give a blue oil. Flash silica gel columnchromatography eluting with ethyl acetate-hexane=1-20 to 1-10 affordedethyl4-(4-fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylateas an yellow oil, which was crystalized upon standing (360 mg, 77.5%).

¹H-NMR (CDCl₃) δ 1.02 (3H, t, J=7 Hz), 1.41 (6H, d, J=7 Hz), 3.29 (1H,septet, J=7 Hz), 4.10 (2H, q, J=7 Hz), 6.42 (1H, d, J=5 Hz), 7.20 (2H,t, J=9 Hz), 7.45-7.51 (3H, m), 10.56 (1H, s).

MS (ESI⁺): m/z 355 (M+H)

EXAMPLE 631

To a solution of N,N-dimethylacetamide (80.1 mg, 0.919 mmol) indichloroethane (1 mL) was added phosphorus oxychloride (141 mg, 0.919mmol) in dichloroethane (0.5 mL) at 0° C. After stirring for 0.5 h, asolution of ethyl4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate(200 mg, 0.613 mmol) in dichloroethane (0.5 mL) was added. The resultingmixture was stirred for 3 days at room temperature. The mixture waspartitioned between ethyl acetate (30 mL) and water (5 mL), and theorganic layer was washed with saturated sodium bicarbonate, brine, driedover anhydrous magnesium sulfate, and evaporated to give an orange gum.Flash silica gel column chromatography eluting with ethylacetate-hexane=1-20 to 1-10 afforded ethyl7-acetyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylateas an yellow gum (144 mg, 63.8%).

¹H-NMR (CDCl₃) δ 1.00 (3H, t, J=7 Hz), 1.41 (6H, d, J=7 Hz), 2.88 (3H,s), 3.09 (1H, septet, J=7 Hz), 4.09 (2H, q, J=7 Hz), 6.40 (1H, d, J=5Hz), 7.19 (2H, t, J=9 Hz), 7.46 (2H, dd, J=3 and 9 Hz), 7.57 (2H, d, J=7Hz).

MS (ESI⁺): m/z 369 (M+H)

EXAMPLE 632

A solution of ethyl4-(4-fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate(100 mg, 0.282 mmol) and sodium borohydride (10.7 mg, 0.282 mmol) inethanol (1 mL) was stirred for 0.5 h under an ice bath. The mixture waspartitioned between ethyl acetate (10 mL) and water (5 mL), and theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate, and evaporateed to give ethyl4-(4-fluorophenyl)-7-hydroxymethyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylateas an yellow gum (89.1 mg, 89.1%).

¹H-NMR (CDCl₃) δ 0.97 (3H, t, J=7 Hz), 1.37 (6H, J=7 Hz), 3.25-3.37 (2H,m), 4.04 (2H, q, J=7 Hz), 5.06 (1H, d, J=7 Hz), 6.32 (1H, d, J=5 Hz),6.78 (1H, d, J=5 Hz), 7.19 (2H, t, J=9 Hz), 7.46 (2H, d, J=4 and 9 Hz).

EXAMPLE 633

To a solution of ethyl4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate(80.0 mg, 0.245 mmol) and N,N-dimethylaminopyridine (29.9 mg, 0.245mmol) in N,N-dimethylformamide (0.5 mL) was added3,7-dinitro-5-(trifluoromethyl)dibenzo[b,d]thiopheniumtrifluoromethanesulfonate (120 mg, 0.245 mmol) at −20° C. The resultingmixture was stirred for 45 min at 0° C. and 12 h at room temperatue.Water (5 mL) and ethyl acetate (10 mL) were added, and the resultingmixture was filtered. The organic layer was washed with brine, driedover anhydrous magnesium sulfate, and evaporated to give a brown gum.Flash silica gel column chromatography eluting with toluene-hexane=1-5to 4-5 afforded ethyl4-(4-fluorophenyl)-2-isopropyl-7-trifluoromethylpyrrolo[1,2-b]pyridazine-3-carboxylateproduct as an yellow gum (46.7 mg, 48.3%).

¹H-NMR (CDCl₃) δ 1.00 (3H, t, J=7 Hz), 1.38 (6H, d, J=7 Hz), 3.26 (1H,septet, J=7 Hz), 4.08 (2H, q, J=7 Hz), 6.33 (1H, d, J=5 Hz), 7.12 (H, d,J=5 Hz), 7.19 (2H, t, J=9 Hz), 7.47 (2H, d, J=4 and 9 Hz).

MS (ESI⁺): m/z 395 (M+H)

EXAMPLE 634

A solution of ethyl4-(4-fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate(200 mg, 0.564 mmol), hydroxylamine hydrochloride (51.0 mg, 0.734 mmol),and sodium formate (69.1 mg, 1.02 mmol) in formic acid (2 mL) wererefluxed for 2 h. The mixture was evaporated to give a green gum. Thegum was partitioned between ethyl acetate (10 mL) and saturated sodiumbicarbonate (5 mL). The organic layer was washed with brine, dried overanhydrous magnesium sulfate, and evaporated to give a green gum. Flashsilica gel column chromatography eluting with ethyl acetate-hexane=1-10to 1-8 gave ethyl7-cyano-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylateas an yellow crystal (144 mg, 72.6%).

¹H-NMR (CDCl₃) δ 1.01 (3H, t, J=7 Hz), 1.41 (6H, d, J=7 Hz), 3.26 (1H,septet, J=7 Hz), 4.09 (2H, q, J=7 Hz), 6.36 (1H, d, J=5 Hz), 7.20 (2H,t, J=9 Hz), 7.28 (1H, d, J=5 Hz), 7.47 (2H, d, J=4 and 9 Hz).

MS (ESI⁺): m/z 398 (M+HCOOH+H)

EXAMPLE 635

A solution of ethyl7-cyano-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate(70.4 mg, 0.200 mmol) in sulfuric acid (1 mL) was stirred for 50 min at70° C. The solution was partitioned between ethyl acetate and water. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate, and evaporated to give a brown gum. Preparative silica gel thinlayer chromatography eluting with ethyl acetate-hexane=1-1 affordedethyl7-aminocarbonyl-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylateas an orange solid (5.2 mg, 7.0%).

¹H-NMR (CDCl₃) δ 0.99 (3H, t, J=7 Hz), 1.41 (6H, d, J=7 Hz), 3.41 (1H,septet, J=7 Hz), 4.08 (2H, q, J=7 Hz), 5.93 (1H, br s), 6.46 (1H, d, J=5Hz), 7.45 (2H, t, J=9 Hz), 7.28 (1H, d, J=5 Hz), 8.90 (1H, br s).

EXAMPLE 636

To a mixture of ethyl4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate(100 mg, 0.306 mmol) and ammonium thiocyanate (28.0 mg, 0.368 mmol) inmethanol (100 mL) was added cerium ammonium nitrate (386 mg, 0.705 mmol)under an ice bath. The mixture was stirred for 30 min. The mixture wasstirred for additional 10 min after adding ammonium thiocyanate (8.2 mg,0.107 mmol). Water (5 mL) was added, and the mixture was extracted withethyl acetate (20 mL). The organic extract was washed with brine, driedover anhydrous magnesium sulfate, and evaporated to give a deep greengum. Flash silica gel column chromatography eluting with ethylacetate-hexane=1-10 to 3-20 afforded ethyl ethyl4-(4-fluorophenyl)-2-isopropyl-7-thiocyanatopyrrolo[1,2-b]pyridazine-3-carboxylateas an yellow gum (89.6 mg, 82.3%).

¹H-NMR (CDCl₃) δ 1.01 (3H, t, J=7 Hz), 1.46 (6H, d, J=7 Hz), 3.36 (1H,septet, J=7 Hz), 4.08 (2H, q, J=7 Hz), 6.23 (1H, d, J=5 Hz), 7.14-7.22(3H, m), 7.16 (2H, t, J=9 Hz), 7.46 (2H, dd, J=4 and 9 Hz).

EXAMPLE 637

To a solution of ethyl4-(4-fluorophenyl)-2-isopropyl-7-thiocyanatopyrrolo[1,2-b]pyridazine-3-carboxylate(77.7 mg, 0.219 mmol) in methanol (0.7 mL) was added 85% potassiumhydroxide (0.3 mg, 0.004 mmol) at room temperature. After stirring for 5min, the mixture was partitioned between ethyl acetate (20 mL) and water(5 mL). The organic layer was washed with brine, dried over anhydrousmagnesium sulfate, and evaporated to give an yellow gum. Preparativesilica gel thin layer chromatography eluting with ethylacetate-hexane=1-7 afforded ethyl4-(4-fluorophenyl)-2-isopropyl-7-(methylthio)pyrrolo[1,2-b]pyridazine-3-carboxylateas an yellow gum (35.9 mg, 44.1%).

¹H-NMR (CDCl₃) δ 0.98 (3H, t, J=7 Hz), 1.41 (6H, d, J=7 Hz), 2.52 (3H,s), 3.32 (1H, septet, J=7 Hz), 4.05 (2H, q, J=7 Hz), 6.35 (1H, d, J=5Hz), 6.89 (1H, d, J=5 Hz), 7.16 (2H, t, J=9 Hz), 7.44 (2H, d, J=4 and 9Hz).

MS (ESI⁺): m/z 373 (M+H)

The following compound(s) was (were) obtained in a similar manner tothat of Example 1

EXAMPLE 6383-(9-ethyl-3-methoxy-5,6-dihydrobenzo[f]pyrrolo[1,2-b]cinnolin-12-yl)benzonitrile

¹H NMR (CDCl₃) δ 1.41 (3H, t, J=8 Hz), 2.91-3.11 (6H, m), 3.78 (3H, s),6.09 (1H, d, J=5 Hz), 6.38 (1H, dd, J=8, 3 Hz), 6.52 (1H, d, J=8 Hz),6.59 (1H, d, J=5 Hz), 6.77 (1H, br s), 7.56 (1H, t, J=8 Hz), 7.67 (1H,br d, J=8 Hz), 7.70-7.77 (2H, m).

EXAMPLE 6394-(3-ethyl-6H-indeno[1,2-e]pyrrolo[1,2-b]pyridazin-11-yl)benzonitrile

¹H NMR (CDCl₃) δ 1.43 (3H, t, J=8 Hz), 3.09 (2H, q, J=8 Hz), 4.11 (3H,s), 6.14 (1H, d, J=5 Hz), 6.64 (1H, d, J=5 Hz), 6.71 (1H, d, J=8 Hz),7.07 (1H, t, J=8 Hz), 7.20-7.30 (1H, overlapped with CDCl₃), 7.49 (1H,d, J=8 Hz), 7.69 (2H, d, J=8 Hz), 7.88 (2H, d, J=8 Hz).

MS (ESI⁺): m/z 336 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 24.

Preparation 352

ethyl 4-methoxy-2-[(5-methyl-3-pyridinyl)carbonyl]-3-oxobutanoate

¹H NMR (CDCl₃) δ 0.97, 1.26 (3H, t, J=7 Hz), 2.40 (3H, s), 3.24, 3.35,3.49 (3H, s), 3.98-4.20 (2H, m), 4.11, 4.20, 4.54 (2H, s), 5.70 (1H, s),7.67, 7.92, 8.02, 8.50-8.66, 8.77, 8.89 (3H, m).

Preparation 353

ethyl 2-[(5-chloro-3-pyridinyl)carbonyl]-4-methoxy-3-oxobutanoate

¹H NMR (CDCl₃) δ 1.00, 1.06, 1.28, 1.35 (3H, t, J=7 Hz), 3.23, 3.43,3.49 (3H, s), 4.05-4.33 (2H, m), 4.56 (2H, s), 7.85, 8.05, 8.22, 8.29,8.58-8.82, 8.85, 9.01, 9.10 (3H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 176.

Preparation 354

tert-butyl3-bromo-5-({1-[(cyanoacetyl)amino]-5-ethyl-1H-pyrrol-2-yl}carbonyl)benzoate

¹H-NMR (CDCl₃) δ 1.29 (34H, t, J=7 Hz), 1.60 (9H, s), 2.61 (2H, q, J=7Hz), 3.64 (2H, s), 6.00 (1H, m), 6.80 (1H, m), 8.03 (1H, m), 8.26 (1H,m), 8.28 (1H, m).

Preparation 355

tert-butyl3-bromo-5-[(5-ethyl-1-{[(methylsulfonyl)acetyl]amino}-1H-pyrrol-2-yl)carbonyl]benzoate

¹H-NMR (CDCl₃) δ 1.29 (3H, t, J=7 Hz), 1.60 (9H, s), 2.60 (2H, q, J=7Hz), 2.92 (3H, s), 4.04 (2H, s), 6.11 (1H, m), 6.78 (1H, m), 8.03 (1H,m), 8.25 (1H, m), 8.27 (1H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 153.

Preparation 356

tert-butyl 3-bromo-5-(chlorocarbonyl)benzoate

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 164.

Preparation 357

tert-butyl 3-bromo-5-[(5-ethyl-1H-pyrrol-2-yl)carbonyl]benzoate

¹H-NMR (CDCl₃) δ 1.32 (3H, t, J=7 Hz), 1.61 (9H, s), 2.74 (2H, q, J=7Hz), 6.10 (1H, m), 6.80 (1H, m), 8.13 (1H, m), 8.26 (1H, m), 8.39 (1H,m), 934 (1H, s, br).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 338.

Preparation 358

tert-butyl 3-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]-5-bromobenzoate

¹H-NMR (CDCl₃) δ 1.29 (3H, t, J=7 Hz), 1.61 (9H, s), 2.76 (2H, q, J=7Hz), 5.74 (2H, s, br), 5.93 (1H, d, J=5 Hz), 6.63 (1H, d, J=5 Hz), 8.05(1H, m), 8.25 (1H, m), 8.29 (1H, m).

Preparation 359

To a solution of tert-butyl 3-bromo-5-iodobenzoate (4.00 g) intetrahydrofuran (30 mL) was added 0.76 M isopropylmagnesium bromide(13.7 mL) in an ice-methanol bath under a nitrogen atmosphere. Afterstirring for 0.5 hour, the mixture was poured onto dryice. The mixturewas warmed to room temperature over 1 hour. The mixture was partitionedbetween EtOAc and 1 N hydrochloric acid. The organic layer was backextracted with 1 N sodium hydroxide (two times). The extract wasacidified by adding concentrated hydrochloric acid, and extracted withchloroform (two times). The organic extract was washed with brine, driedover MgSO₄, and evaporated to give3-bromo-5-(tert-butoxycarbonyl)benzoic acid as a pale brown solid (529mg).

3-bromo-5-(tert-butoxycarbonyl)benzoic acid

¹H-NMR (DMSO-d₆) δ 1.57 (9H, s), 8.21 (1H, s), 8.25 (1H, s), 8.37 (1H,s).

Preparation 360

To a vigirously stirred suspension of poudered MgSO₄ (7.36 g) indichloromethane (50 mL) was added sulfuric acid (0.758 mL) at roomtemperature. After stirring for 15 minutes, to the mixture was added3-bromo-5-iodobenzoic acid (5.00 g) followed by tert-butanol (7.31 mL).The mixture was stirred for 3 days at room temperature. The mixture waspartitioned between EtOAc and water. The organic layer was washed withsatd. NaHCO₃ and brine, dried over MgSO₄, and evaporated to givetert-butyl 3-bromo-5-iodobenzoate as pale purple crystals (4.44 g).

tert-butyl 3-bromo-5-iodobenzoate

¹H-NMR (CDCl₃) δ 1.58 (9H, s), 8.00 (1H, m), 8.06 (1H, m), 8.22 (1H, m).

Preparation 361

To a suspension of lithium (316 mg) in ether (10 mL) was addedcyclopropylbromide (250 g) in ether (10 mL) over 20 min in amethanol-ice bath under a nitrogen atmosphere. The mixture was stirredfor 0.5 hour in an ice bath. The mixture was cooled in a dryice-acetonebath. To the mixture was added a solution of triisopropoxyborane (5.05g) in tetrahydrofuran (5 mL) over 15 minutes. The mixture was alowed towarme to room temperature over 2 hours. The reaction was quenced byadding hydrochloric acid. The organic solvent was evaporated off, andthe residual solution was extracted with ether (30 mL, five times). Thecombined extract was dried over MgSO₄, and evaporated to give a whitesolid (968 mg). The solid was triturated in cold hexanes to givecyclopropylboronic acid as a white powder (789 mg).

Cyclopropylboronic Acid

¹H-NMR (DMSO-d₆) δ −0.40 (1H, m), 0.32 (2H, m), 0.39 (2H, m), 7.28 (2H,s).

The following compound(s) was (were) obtained in a similar manner tothat of Example 21.

EXAMPLE 640 ethyl7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylate

¹H NMR (CDCl₃) δ 0.99 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz), 2.41 (3H,s), 3.06 (2H, q, J=7 Hz), 3.38 (3H, s), 4.06 (2H, q, J=7 Hz), 4.75 (2H,s), 6.33 (1H, d, J=4 Hz), 6.71 (1H, d, J=4 Hz), 7.61 (1H, s), 8.52 (1H,d, J=2 Hz), 8.54 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 354.

EXAMPLE 641 ethyl4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3-carboxylate

¹H NMR (300 MHz, CDCl₃) δ 1.04 (3H, t, J=7 Hz), 1.38 (3H, t, J=7 Hz),3.06 (2H, q, J=7 Hz), 3.39 (3H, s), 4.09 (2H, q, J=7 Hz), 4.76 (2H, s),6.33 (1H, d, J=4 Hz), 6.75 (1H, d, J=4 Hz), 7.81 (1H, dd, J=2, 2 Hz),8.57 (1H, d, J=2 Hz), 8.68 (1H, d, J=2 Hz).

MS (m/z) 374 (M+1).

The following compound(s) was (were) obtained in a similar manner tothat of Example 0.76.

EXAMPLE 642(2E)-3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylicacid

¹H NMR (CDCl₃) δ 1.39 (3H, t, J=7 Hz), 2.43 (3H, s), 3.07 (2H, q, J=7Hz), 3.51 (3H, s), 4.65 (2H, s), 5.97 (1H, d, J=16 Hz), 6.27 (1H, d, J=4Hz), 6.71 (1H, d, J=4 Hz), 7.61 (1H, s), 7.72 (1H, d, J=16 Hz), 8.46(1H, d, J=2 Hz), 8.57 (1H, d, J=2 Hz).

MS (ESI⁺): m/z 352.

EXAMPLE 643(2E)-3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylicacid

¹H NMR (300 MHz, CDCl₃) δ 1.39 (3H, t, J=7 Hz), 3.07 (2H, q, J=7 Hz),3.51 (3H, s), 4.65 (2H, s), 5.97 (1H, d, J=16 Hz), 6.27 (1H, d, J=4 Hz),6.75 (1H, d, J=4 Hz), 7.69 (1H, d, J=16 Hz), 7.78 (1H, dd, J=2, 2 Hz),8.54 (1H, d, J=2 Hz), 8.71 (1H, d, J=2 Hz).

MS (m/z) 400 (M+1).

EXAMPLE 6444-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid

¹H-NMR (CDCl₃) δ 0.78 (2H, m), 1.10 (2H, m), 1.37 (3H, t, J=7 Hz), 1.73(2H, m), 1.98 (1H, m), 2.23 (2H, m), 2.62 (2H, m), 3.02 (2H, q, J=7 Hz9, 3.46 (3H, s), 4.65 (2H, q, J=7 Hz), 5.88 (1H, d, J=5 Hz), 6.57 (1H,d, J=5 Hz), 7.36 (1H, m), 8.41 (1H, m), 8.47 (11H, m).

EXAMPLE 6455-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid

¹H-NMR (CDCl₃) δ 0.75 (2H, m), 1.08 (2H, m), 1.37 (3H, t, J=7 Hz),1.40-1.57 (4H, m), 1.96 (1H, m), 2.18 (2H, m), 2.51 (2H, m), 3.02 (2H,q, J=7 Hz), 3.45 (3H, s), 4.61 (2H, m), 5.87 (1H, d, J=5 Hz), 6.56 (1H,d, J=5 Hz), 7.34 (1H, m), 8.39 (1H, m), 8.50 (1H, m).

EXAMPLE 6463-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid

¹H-NMR (DMSO-d₆) δ 0.76 (2H, m), 1.08 (2H, m), 1.37 (3H, t, J=7 Hz),1.95 (1H, m), 2.48 (2H, m), 2.87 (2H, m), 3.02 (2H, q, J=7 Hz), 3.47(3H, s), 4.66 (2H, m), 5.90 (1H, d, J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.35(1H, m), 8.40 (1H, m), 8.48 (1H, m).

EXAMPLE 6475-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-oxopentanoicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=8 Hz), 1.73-1.85 (2H, m), 2.26 (2H, t,J=8 Hz), 2.36 (2H, t, J=8 Hz), 2.46 (3H, s), 3.04 (2H, q, J=8 Hz), 6.33(1H, d, J=5 Hz), 6.70 (1H, d, J=5 Hz), 7.34 (1H, br d), 7.45(1H, br s),8.53 (1H, d, J=6 Hz).

EXAMPLE 648(2E)-3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acrylicacid

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=8 Hz), 2.67 (3H, s), 3.05 (2H, q, J=8Hz), 5.79 (1H, d, J=15 Hz), 6.19 (1H, d, J=5 Hz), 6.67 (1H, d, J=5 Hz),7.24-7.29 (1H, overlappled with CDCl₃), 7.40 (1H, br s), 7.51 (1H, d,J=15 Hz), 8.55 (1H, d, J=5 Hz).

The following compound(s) was (were) obtained in a similar manner tothat of Example 146.

EXAMPLE 649 ethyl(2E)-3-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acrylate

¹H NMR (CDCl₃) δ 1.27 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 2.65 (3H,s), 3.04 (2H, q, J=8 Hz), 4.17 (2H, q, J=8 Hz), 5.76 (1H, d, J=15 Hz),6.16 (1H, d, J=5 Hz), 6.65 (1H, d, J=5 Hz), 7.24-7.29 (1H, overlappledwith CDCl₃), 7.40 (1H, br s), 7.53 (1H, d, J=15 Hz), 8.53 (1H, d, J=5Hz).

MS (ESI⁺): m/z 370 (M+H).

The following compound(s) was (were) obtained in a similar manner tothat of Example 181.

EXAMPLE 650 tert-butyl3-bromo-5-(3-cyano-7-ethyl-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl)benzoate

¹H-NMR (CDCl₃) δ 1.36 (3H, t, J=7 Hz), 2.94 (2H, q, J=7 Hz), 6.57 (1H,d, J=5 Hz), 6.72 (1H, d, J=5 Hz), 7.94 (1H, m), 8.20 (1H, m), 8.38 (1H,m).

EXAMPLE 651 tert-butyl3-bromo-5-[7-ethyl-3-(methylsulfonyl)-2-oxo-1,2-dihydropyrrolo[1,2-b]pyridazin-4-yl]benzoate

¹H-NMR (CDCl₃) δ 1.35 (3H, t, J=7 Hz), 3.02 (2H, q, J=7 Hz), 3.06 (3H,s), 6.24 (1H, d, J=5 Hz), 6.70 (1H, d, J=5 Hz), 7.23 (1H, m), 7.94 (1H,m), 8.25 (1H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 183.

EXAMPLE 652 tert-butyl3-bromo-5-(3-cyano-7-ethyl-2-{[(trifluoromethyl)sulfonyl]oxy}pyrrolo[1,2-b]pyridazin-4-yl)benzoate

¹H-NMR (CDCl₃) δ 1.39 (3H, t, J=7 Hz), 1.61 (9H, s), 3.02 (2H, q, J=7Hz), 6.81 (1H, d, J=5 Hz), 7.00 (1H, d, J=5 Hz), 7.96 (1H, m), 8.21 (1H,m), 8.33 (1H, m).

EXAMPLE 653 tert-butyl3-bromo-5-(7-ethyl-3-(methylsulfonyl)-2-{[(trifluoromethyl)sulfonyl]oxy}pyrrolo[1,2-b]pyridazin-4-yl)benzoate

¹H-NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 1.59 (9H, s), 3.01 (2H, q, J=7Hz), 3.22 (3H, s), 6.46 (1H, d, J=5 Hz), 7.12 (1H, d, J=5 Hz), 7.67 (1H,m), 7.90 (1H, m), 8.23 (1H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 184.

EXAMPLE 654 tert-butyl3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate

¹H-NMR (CDCl₃) δ 1.35 (3H, t, J=7 Hz), 1.60 (9H, s), 2.01 (4H, m), 2.93(2H, q, J=7 Hz), 3.73 (4H, m), 6.32 (1H, d, J=5 Hz), 6.58 (1H, d, J=7Hz), 7.86 (1H, m), 8.12 (1H, m), 8.24 (1H, m).

EXAMPLE 655 tert-butyl3-bromo-5-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J=7 Hz), 1.58 (9H, s), 1.99 (4H, m), 2.98(2H, q, J=7 Hz), 3.21 (3H, s), 3.52 (4H, m), 6.30 (1H, d, J=5 Hz), 6.66(1H, d, J=5 Hz), 7.76 (1H, m), 8.00 (1H, m), 8.19 (1H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 147.

EXAMPLE 656 ethyl(2E)-3-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylate

¹H NMR (300 MHz, CDCl₃) δ 1.27 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz),3.07 (2H, q, J=7 Hz), 3.51 (3H, s), 4.18 (2H, q, J=7 Hz), 4.64 (2H, s),5.97 (1H, d, J=16 Hz), 6.24 (1H, d, J=4 Hz), 6.72 (1H, d, J=4 Hz), 7.61(1H, d, J=16 Hz), 7.76 (1H, dd, J=2, 2 Hz), 8.54 (1H, d, J=2 Hz), 8.68(1H, d, J=2 Hz).

The following compound(s) was (were) obtained in a similar manner tothat of Example 205.

EXAMPLE 657(4E)-5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]-4-pentenoicacid

¹H NMR (300 MHz, CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.25-2.41 (4H, m), 3.05(2H, q, J=7 Hz), 3.50 (3H, s), 4.57 (2H, s), 5.53 (1H, dd, J=16, 7 Hz),6.13 (1H, d, J=4 Hz), 6.36 (1H, d, J=16 Hz), 6.65 (1H, d, J=4 Hz), 7.80(1H, s), 8.54 (1H, br s), 8.62 (1H, br s).

MS (m/z) 400 (M+1).

The following compound(s) was (were) obtained in a similar manner tothat of Preparation 153.

EXAMPLE 6584-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carbonylchloride

The following compound(s) was (were) obtained in a similar manner tothat of Example 244.

EXAMPLE 6597-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carbaldehyde

¹H NMR (CDCl₃) δ 1.40 (3H, t, J=7 Hz), 2.45 (3H, s), 3.12 (2H, q, J=7Hz), 3.56 (3H, s), 4.96 (2H, s), 6.51 (1H, d, J=4 Hz), 6.80 (1H, d, J=4Hz), 7.62 (1H, s), 8.54 (1H, s), 8.61 (1H, s), 9.79 (1H, s).

MS (ESI⁺): m/z 310.

EXAMPLE 6604-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazine-3-carbaldehyde

¹H NMR (300 MHz, CDCl₃) δ 1.41 (3H, t, J=7 Hz), 3.12 (2H, q, J=7 Hz),3.54 (3H, s), 4.94 (2H, s), 6.50 (1H, d, J=4 Hz), 6.84 (1H, d, J=4 Hz),7.81 (1 (H, dd, J=2, 2 Hz), 8.59 (1H, d, J=2 Hz), 8.74 (1H, d, J=2 Hz),9.85 (1H, s).

The following compound(s) was (were) obtained in a similar manner tothat of Example 533.

EXAMPLE 661[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol

¹H NMR (CDCl₃) δ 1.38 (3H, t, J=7 Hz), 2.43 (3H, s), 3.05 (2H, q, J=7Hz), 3.52 (3H, s), 4.37-4.51 (2H, br), 4.66-4.78 (2H, br), 6.20 (1H, d,J=4 Hz), 6.67 (1H, d, J=4 Hz), 7.75 (1H, s), 8.54 (1H, s), 8.60 (1H, s).

MS (ESI⁺): m/z 312.

EXAMPLE 662[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]methanol

¹H NMR (300 MHz, CDCl₃) δ 1.38 (3H, t, J=7 Hz), 3.05 (2H, q, J=7 Hz),3.53 (3H, s), 4.41 (2H, d, J=6 Hz), 4.77 (2H, s), 6.22 (1H, d, J=4 Hz),6.70 (1H, d, J=4 Hz), 7.97 (1H, dd, J=2, 2 Hz), 8.69-8.71 (2H, m).

MS (m/z) 332 (M+1).

EXAMPLE 663

A mixture of7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carbaldehyde(48 mg) and ethyl (triphenylphosphoranylidene)acetate (56.8 mg) in THF(3 mL) was stirred at ambient temperature for 2 hours. After evaporationof solvent, the residue was purified by silica gel column chromatographyeluting with a mixture of hexane and AcOEt (5:1-2:1) to give ethyl(2E)-3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylateas a yellow powder (30 mg).

ethyl(2E)-3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylate

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7 Hz), 1.39 (3H, t, J=7 Hz), 2.42 (3H,s), 3.07 (2H, q, J=7 Hz), 3.51 (3H, s), 4.12 (2H, q, J=7 Hz), 4.64 (2H,s), 5.97 (1H, d, J=16 Hz), 6.24 (1H, d, J=4 Hz), 6.70 (1H, d, J=4 Hz),7.55 (1H, s), 7.63 (1H, d, J=16 Hz), 8.47 (1H, d, J=2 Hz), 8.55 (1H, d,J=2 Hz).

MS (ESI⁺): m/z 380.

EXAMPLE 664

To a mixture of ethyl4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate(75.0 mg), cyclopropylboronic acid (18.2 mg), tricyclohexylphosphine(457 mg), and potassium phosphate (104 mg) in toluene-water (1 mL-0.2mL) was added palladium acetate (1.83 mg). The mixture was stirred for 2hours at 100° C. The mixture was partitioned between EtOAc and water.The organic layer was washed with brine, dried over MgSO₄, andevaporated. Preparative silica gel thin layer chtomatography(EtOAc-hexanes=1-3) afforded ethyl4-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyolo[1,2-b]pyridazin-3-yl]butanoateasan yellow gum (60.9 mg).

ethyl4-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoate

¹H-NMR (CDCl₃) δ 0.76 (2H, m), 1.07 (2H, m), 1.20 (3H, t, J=7 Hz), 1.37(3H, t, J=7 Hz), 1.68 (2H, m), 1.96 (1H, m), 2.17 (2H, m), 2.56 (2H, m),3.02 (2H, q, J=7 Hz), 3.46 (3H, s), 4.03 (2H, q, J=7 Hz), 4.65 (2H, m),5.90 (1H, d, J=5 Hz), 6.57 (1H, d, J=5 Hz), 7.30 (1H, m), 8.40 (1H, m),8.51 (1H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 664.

EXAMPLE 665 ethyl5-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate

¹H-NMR (CDCl₃) δ 0.76 (2H, m), 1.08 (2H, m), 1.23 (3H, t, J=7 Hz),1.35-1.57 (7H, m), 1.96 (1H, m), 2.16 (2H, t, J=7 Hz), 2.53 (2H, m),3.03 (2H, q, J=7 Hz), 3.46 (3H, s), 4.08 (2H, q, J=7 Hz), 4.62 (2H, s),5.89 (1H, d, J=5 Hz), 6.56 (1H, d, J=5 Hz), 7.29 (1H, m), 8.40 (1H, m),8.52 (1H, m).

EXAMPLE 666 ethyl3-[4-(5-cyclopropyl-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoate

¹H-NMR (CDCl₃) δ 0.76 (2H, m), 1.08 (2H, m), 1.19 (3H, t, J=7 Hz), 1.37(3H, t, J=7 Hz), 1.97 (1H, m), 2.38 (2H, m), 2.85 (2H, m), 3.02 (2H, q,J=7 Hz), 3.46 (3H, s), 4.04 (2H, q, J=7 Hz), 4.64 (2H, s), 5.92 (1H, d,J=5 Hz), 6.59 (1H, d, J=5 Hz), 7.29 (1H, m), 8.40 (1H, m), 8.53 (1H, m).

EXAMPLE 667 tert-butyl3-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]-5-cyclopropylbenzoate

¹H-NMR (CDCl₃) δ 0.81 (2H, m), 1.03 (2H, m), 1.35 (3H, t, J=7 Hz), 1.59(9H, s), 1.94-2.08 (5H, m), 2.94 (2H, q, J=7 Hz), 3.68-3.77 (4H, m),6.35 (1H, j, J=5 Hz), 6.55 (1H, d, J=5 Hz), 7.43 (1H, s), 7.84 (1H, s),7.97 (1H, s).

EXAMPLE 668

A solution of tert-butyl3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoate(16.0 mg) in trifluoroacetic acid (0.5 mL) was stirred for 0.5 hour atroom temperature. The reaction was quenched by adding water. The mixturewas neutralized by adding NaOH (pH=3). The mixture was extracted withEtOAc. The extract was washed with brine, dried over MgSO₄, andevaporated to give a greenish yellow solid. The solid was triturated inhexanes-CHCl₃ (2-1) to afford3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoicacid as an yellow powder (10.8 mg).

3-bromo-5-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoicacid

¹H-NMR (CDCl₃+CD₃OD) δ 1.36 (3H, t, J=7 Hz), 2.01 (4H, m), 2.94 (2H, q,J=7 Hz), 3.72 (4H, m), 636 (1H, d, J=5 Hz), 6.60 (1H, d, J=5 Hz), 7.92(1H, m), 8.23 (1H, m), 8.35 (1H, m).

The following compound(s) was (were) obtained in a similar manner tothat of Example 668.

EXAMPLE 669 3-[3-cyano-7-ethyl-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]-5-cyclopropylbenzoic acid

¹H-NMR (CDCl₃+CD₃OD) δ 0.81 (2H, m), 1.05 (2H, m), 1.35 (3H, t, J=7 Hz),2.01 (5H, m), 2.94 (2H, q, J=7 Hz), 7.73 (4H, m), 637 (1H, d, J=5 Hz),6.57 (1H, d, J=5 Hz), 6.98 (1H, s), 7.90 (1H, s), 8.08 (1H, s).

EXAMPLE 6703-bromo-5-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinyl)pyrrolo[1,2-b]pyridazin-4-yl]benzoicacid

¹H-NMR (CDCl₃+CD3OD) δ 1.37 (3H, t, J=7 Hz), 1.98 (4H, m), 2.99 (2H, q,J=7 Hz), 3.20 (3H, s), 3.56 (4H, m), 6.32 (1H, d, J=5 Hz), 6.67 (1H, d,J=5 Hz), 7.80 (1H, m), 8.08 (1H, m), 8.30 (1H, m).

EXAMPLE 671

To a 3-necked frask containing Zn—Cu couple was added a solution ofethyl 4-iodobutanoate (369 mg) in toluene (3 mL) andN,N-dimethylacetamide (0.2 mL) at ambient temperature under N₂. Themixture was stirred at the temperature for 1 h and then at 60° C. for 3h. A suspension of tetrakis(triphenylphosphine)palladium (44 mg) intoluene (0.5 mL) was added and stirred for 5 min. After removal of anoil bath, the mixture was cooled in an ice-water bath. To this mixturewas added a solution of4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carbonylchloride (212 mg) in DCM (1 mL) dropwise. After 10 min, the reactionmixture was stirred at ambient temperature for 2 h. The reaction mixturewas partitioned between AcOEt and H₂O. The organic layer was washed withsat. NaHCO₃ and brine, dried over MgSO₄, and evaporated in vacuo. Theresidue was purified by flash silica gel chromatography (silica gel, 80mL) eluted with hexane-AcOEt=10-1 and 5-1 to give ethyl5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-oxopentanoateas yellow amorphous (143 mg).

ethyl5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-oxopentanoate

¹H NMR (CDCl₃) δ 1.23 (3H, t, J=8 Hz), 1.38 (3H, t, J=8 Hz), 1.71-1.84(2H, m), 2.17 (3H, t, J=8 Hz), 2.32 (3H, t, J=8 Hz), 2.46 (3H, s), 3.04(2H, q, J=8 Hz), 4.06 (2H, q, J=8 Hz), 6.32 (1H, d, J=5 Hz), 6.70 (1H,d, J=5 Hz), 7.32 (1H, dd, J=5, 1), 7.46 (1H, br s), 8.53 (1H, d, J=5Hz).

EXAMPLE 672

To a solution of5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-oxopentanoicacid (47 mg) in EtOH (1 mL) was added sodium borohydride (5 mg) in anice-water bath under N₂. After 10 min, the mixture was stirred atambient temperature. After 1 h, another odium borohydride (5 mg) wasadded. After 2 h, the reaction mixture was partitioned between CHCl₃ andH₂O. The aqueous layer was extracted with CHCl₃ twice. The combinedorganic layer was dried over MgSO₄ and evaporated in vacuo. The residuewas purified by p-TLC (CHCl₃-MeOH=10-1) to give5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-hydroxypentanoicacid as yellow amorphous (28 mg).

5-[4-(2-chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-5-hydroxypentanoicacid

¹H NMR (CDCl₃) δ 1.36 (3H, t, J=8 Hz), 1.46-1.83 (3H, m), 1.95 (1H, m),2.70 (3H, br s), 3.01 (2H, q, J=8 Hz), 4.63 (1H, m), 5.85 (1H, m), 6.55(1H, d, J=5 Hz), 7.18-7.29 (1H, overlapped with CDCl₃), 7.34 (1H, d, J=2Hz), 8.49 (1H, d, J=5 Hz).

1. A compound of the formula I or a pharmaceutically acceptable saltthereof, or a prodrug thereof:

wherein R¹ is (1) a carboxy or a protected carboxy, (2) —CONR⁵R⁶, (3) ahydroxy or a lower alkoxy, (4) an amino, a cyclo(lower)alkylamino or amono- or di(lower)alkylamino optionally substituted by a lower alkoxy,(5) a trihalo(lower)alkyl, (6) a trihalo(lower)alkylsulfonyloxy or anarylsulfonylamino, (7) a substituted lower alkyl or an unsubstitutedlower alkyl, (8) a substituted aryl or an unsubstituted aryl, or (9) asubstituted heterocyclic group or an unsubstituted heterocyclic group,R² is R⁷ or -(A¹)p-X-A²-R⁷, wherein p is an integer of 0 or 1 A¹ is a(C₁-C₂)alkylene or —CH═CH—; A² is —(CH₂)n- or —(CH═CH)m- wherein n is aninteger which may range from 1 to 6, and m is an integer which may rangefrom 1 to 3; X is a single bond, —O—, —NR⁸—, —C(═O)—, —C(═NR⁹)— or ahydroxy(C₁-C₂)alkylene wherein R⁸ is a hydrogen or a lower alkyl, and R⁹is a substituted N-containing heterocyclic group, an unsubstitutedN-containing heterocyclic group, and R⁷ is (1) a hydrogen, (2) asubstituted aryl or an unsubstituted aryl, (3) a substitutedheterocyclic group or an unsubstituted heterocyclic group, (4) acarboxy, a protected carboxy or CONR¹⁰R¹¹, (5) an acyl or ahalocarbonyl, (6) a cyano, (7) an amino, a protected amino, a or mono-or di(lower)alkylamino, (8) a hydroxy, an aryloxy, an acyloxy or a loweralkyl optionally substituted by a hydroxy or an acyloxy, (9) a loweralkylthio, a lower alkylsulfinyl or a lower alkylsulfonyl, or (10)—O—R¹², or R¹ and R² are combined together to form a lower alkylene or alower alkenylene group which is optionally interrupted by an amino or asulfonyl, and optionally with a benzene ring, and optionally substitutedby the group consisting of a lower alkyl, a hydroxy, an oxo, and a loweralkoxy, R³ is a substituted aryl, an unsubstituted aryl, a substitutedheterocyclic group, or an unsubstituted heterocyclic group, R⁴ is ahydrogen, a halogen, a cyano, a carbamoyl, an acyl, a thiocyanate, alower alkylthio, a lower alkenyl, a hydroxyl(lower)alkyl, atrihalo(lower)alkyl, or a lower alkyl, R⁵, R⁶, R¹⁰ and R¹¹ eachindependently represents a hydrogen, a lower alkylsulfonyl, aheterocyclic group, or a lower alkyl optionally substituted by ahydroxy, an alkoxy, a sulfo, a carboxy, a protected carboxy or —R¹⁷ oralternatively R⁵ and R⁶ or R¹⁰ and R¹¹, together with a nitrogen atom towhich they are attached, represent a N-containing heterocyclic group,and R¹² and R¹⁷ are each independently a group derived from a protectedsugar or an unprotected sugar by removal of the hydroxy group therefrom,wherein if R¹ is a methyl or a phenyl; R² is not a hydrogen; R³ is not aphenyl; and R⁴ is not a hydrogen.
 2. A compound of claim 1, wherein R¹is (1) a carboxy or a protected carboxy, (2) —CONR⁵R⁶ wherein R⁵ and R⁶each independently represents a lower alkyl, or alternatively R⁵ and R⁶,together with a nitrogen atom to which they are attached represents asaturated 5- or 6-membered heteromonocyclic group containing 1 to 2nitrogen atom(s), (3) a hydroxy or a lower alkoxy, (4) an amino, a cyclo(lower) alkylamino, or a mono- or di(lower)alkylamino optionallysubstituted by a lower alkoxy, (5) a trihalo(lower)alkyl, (6) atrihalo(lower)alkylsulfonyloxy or an arylsulfonylamino, (7) a loweralkyl optionally substituted by (i) a halogen; (ii) a carboxy; (iii) aprotected carboxy; (iv) a cyano; (v) a carbamoyl; (vi) —OCONR¹⁵R¹⁶wherein R¹⁵ and R¹⁶ each independently represents a hydrogen, an aryl ora lower alkyl optionally substituted by an aryl, or R¹⁵ and R¹⁶,together with the nitrogen atom to which they are attached, represents asaturated 5- or 6-membered heteromonocyclic group containing 1 to 2nitrogen atom(s) and also optionally containing an oxygen atom; (vii) alower alkylthio; (viii) a lower alkylsulfonyl; (ix) a loweralkylsulfonyloxy; (x) a lower alkylsulfonylamino; (xi) a mono- ordi(lower)alkylamino optionally substituted by a hydroxy, a lower alkoxy,an aryloxy, or a substituted or an unsubstituted aryl; (xii) an amino;(xiii) an acylamino; (xiv) a protected amino; (xv) a hydroxy; (xvi) anacyloxy; (xvii) a cyclo(lower)alkyloxy; (xviii) an aryloxy; (xix) anaryl; (xx) a saturated or unsaturated 5- or 6-membered heteromonocyclicgroup containing 1 to 3 nitrogen atom(s) and also optionally containingan oxygen atom or a sulfur atom which is optionally substituted by alower alkyl, a hydroxy(lower)alkyl, an aryl or an oxo; or (xxi) a loweralkoxy optionally substituted by a carboxy, a protected carboxy, ahydroxy, a protected hydroxy, a lower alkoxy, a cyclo(lower)alkyl, asubstituted of aryl an unsubstituted aryl, a saturated or an unsaturated5- or 6-membered heteromonocyclic group containing 1 to 2 nitrogenatom(s) optionally substituted by a lower alkyl, or —CONR¹³R¹⁴ whereinR¹³ and R¹⁴ each independently represents a hydrogen or a lower alkyloptionally substituted by an aryl, or R¹³ and R¹⁴, together with anitrogen atom to which they are attached, represents a saturated 5- or6-membered heteromonocyclic group containing 1 to 2 nitrogen atom(s) andalso optionally containing an oxygen atom, (8) an aryl optionallysubstituted by the substituent(s) selected from the group consisting ofa halogen, or (9) a saturated or an unsaturated 5- or 6-memberedheteromonocyclic group optionally substituted by a lower alkyl or ahalogen, R² is R⁷ or -(A¹)p-X-A²-R⁷ wherein p is
 0. or 1; A¹ is a(C₁-C₂)alkylene or —CH═CH—; A₂ is —(CH₂)n- or —(CH═CH)m- wherein n is aninteger which may range from 1 to 6, and m is an integer which may rangefrom 1 to 3; X is a single bond, —O—, —NR⁸—, —C(═O)—, —C(═NR⁹)— or ahydroxy(C₁-C₂)alkylene; wherein R⁸ is a hydrogen or a lower alkyl, andR⁹ is a substituted pyrrolyl, or an unsubstituted pyrrolyl R⁷ is (1) ahydrogen, (2) an aryl optionally substituted by a lower alkoxy, (3) anunsaturated heteromonocyclic group containing 1 to 2 nitrogen atom(s),(4) a carboxy, an esterified carboxy or —CONR¹⁰R¹¹ wherein R¹⁰ and R¹¹each independently represents a hydrogen, a lower alkylsulfonyl, anunsaturated heteromonocyclic group containing 1 to 2 nitrogen atom(s) ora lower alkyl optionally substituted by a hydroxy, an alkoxy, a carboxy,a protected carboxy, a sulfo or —R¹⁷, or alternatively R¹⁰ and R¹¹,together with a nitrogen atom to which they are attached, represents asaturated 5- or 6-membered heteromonocyclic group containing 1 to 2nitrogen atom(s) and also optionally containing an oxygen atom includinga morpholinyl, (5) an acyl or a halocarbonyl, (6) a cyano, (7) an amino,a protected amino or a mono- or di(lower)alkylamino, (8) a hydroxy, anaryloxy, an acyloxy or a lower alkoxy optionally substituted by ahydroxy or an acyloxy, (9) a lower alkylthio, a lower alkylsulfinyl or alower alkylsulfonyl, or (10) —O—R¹², or

is represents by the following formula:

R³ is (1) an aryl optionally substituted by at least one substituent(s)selected from the group consisting of (i) a halogen, (ii) a carboxy,(iii) a protected carboxy, (iv) a cyano, (v) —CONR¹⁵R¹⁶ wherein R¹⁵ andR¹⁶ each independently represents a hydrogen, a lower alkyl optionallysubstituted by a hydroxy, (vi) a lower alkyl, (vii) a cyclo(lower)alkyl,(viii) a hydroxy(lower)alkyl, (ix) a lower alkoxy, (x) atrihalo(lower)alkyl, (xi) an unsaturated 5- or 6-memberedheteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 2nitrogen atom(s), (xii) a lower alkylsulfonyl, (xiii) a nitro, (xiv) asulfamoyl, and (xv) a protected sulfamoyl; or (2) a heterocyclic groupselected from the group consisting of a pyridinyl, a pyrazinyl, anoxazolyl, an isooxazolyl, a furanyl, a thienyl, a quinolinyl, abenzofuranyl and a benzothienyl, wherein said heterocyclic group isoptionally substituted by at least one substituent(s) selected from thegroup consisting of (i) a lower alkyl, (ii) a cyclo(lower)alkyl, (iii) alower alkoxy, (iv) an acyl, (v) an amino, (vi) a mono- ordi(lower)alkylamino, (vii) a protected amino, (viii) a cyano, (ix) acarboxy, (x) a protected carboxy, (xi) —CONR¹⁵R¹⁶ wherein R¹⁵ and R¹⁶each independently represents a hydrogen, a lower alkyl optionallysubstituted by a hydroxy, (xii) a lower alkenyl optionally substitutedby a lower alkoxy, (xiii) a halogen, (xiv) a lower alkylthio and (xv) ahydroxyl; R⁴ is a hydrogen, a halogen, a cyano, a carbamoyl, an acyl, athiocyanate, a lower alkylthio, a lower alkenyl, a hydroxyl(lower)alkyl,a trihalo(lower)alkyl, or a lower alkyl, R¹² and R¹⁷ are eachindependently a group derived from a protected sugar, or an unprotectedsugar by removal of a hydroxy group therefrom.
 3. The compound of claim2, wherein R⁴ is a lower alkyl.
 4. The compound of claim 3, wherein R¹is (1) a mono- or di(lower)alkylamino, (2) a phenyl, (3) a saturated orunsaturated 5 to 6 membered heteromonocyclic group selected from thegroup consisting of a pyrrolidinyl, a pyrrolyl, an oxazolyl, anisooxazolyl, a thiazolyl, a furanyl, a thienyl, and a pyridinyl, or (4)a lower alkyl optionally substituted by (i) a lower alkoxy or (ii) asaturated 5- or 6-membered heteromonocyclic group selected from thegroup consisting of a piperazinyl and a morpholinyl, wherein the loweralkoxy is optionally substituted by a cyclo(lower)alkyl or a pyridinyl.5. The compound of claim 4, wherein R¹ is R⁷ or -A²-R⁷, wherein A² is—(CH2)n- or —(CH═CH)m- wherein n is an integer which may range from 2 to6, and m is an integer of 1 or 2, and R⁷ is a hydrogen, a lower alkylsulfonyl, a carboxy, an esterified carboxy or a pyridinyl, R³ is (1) aphenyl optionally substituted by a lower alkyl, a cyclo(lower)alkyl, alower alkoxy, a halogen, a cyano, or a carbamoyl; or (2) a quinolinyl;or a pyridinyl substituted by a lower alkyl, a cyclo(lower)alkyl, alower alkoxy, a carbamoyl or a halogen.
 6. The compound of claim 5,wherein R¹ is a phenyl, a pyrrolyl, an isooxazolyl, a furanyl, athienyl, a lower alkyl optionally substituted by a lower alkoxy, apiperazinyl or a morpholinyl, wherein a lower alkoxy is optionallysubstituted by a cyclo(lower)alkyl or a pyridinyl, R² is —(CH2)n-R⁷,wherein n is an integer which may range from 2 to 5, and R⁷ is a carboxyor an esterified carboxy, and R³ is (1) a phenyl optionally substitutedby a lower alkyl, a cyclo(lower)alkyl, a lower alkoxy, a halogen, acyano, or a carbamoyl; or (2) a pyridinyl substituted by a lower alkyl,a cyclo(lower)alkyl, a lower alkoxy, a carbamoyl or a halogen.
 7. Thecompound of claim 5, which is (1)3-[7-Ethyl-2-methyl-3-(4-pyridinyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile, (2)3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile, (3)4-[7-Ethyl-2-methyl-3-(methylsulfonyl)-pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile,(4) 3-[7-Ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazin-4-yl]benzamide, (5)Ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate,(6)2-{[4-(3-Chlorophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]methyl}-1,3-propanediol,(7)3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid, (8)5-[7-Ethyl-2-methyl-4-(6-quinolinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, (9)5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, (10)5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, (11)5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, (12)3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid, (13)5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, (14) Ethyl(2E)-3-[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]-2-propenoate,(15)6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoicacid, (16)3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid, (17)4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid, (18)5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, (19)5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid, (20)4-{4-(5-chloro-3-pyridinyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}butanoic acid, (21)4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid, (22)4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid, (23)5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, of (24)5-{4-(3-cyanophenyl)-7-ethyl-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid, or a pharmaceutically acceptable salt thereof.
 8. The compound ofclaim 6, which is (1) ethyl5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate,(2)3-[4-(3-Chlorophenyl)-7-ethyl-2-phenyl-pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid, (3)5-[4-(2-Chloro-4-pyridinyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, (4)5-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, (5)5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, (6)3-[7-Ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid, (7)5-[4-(5-Bromo-3-pyridinyl)-7-ethyl-2-(4-morpholinylmethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, (8)6-{4-[4-(aminocarbonyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}hexanoicacid, (9)3-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoicacid, (10)4-[4-(5-bromo-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoicacid, (11)5-[2-[(cyclohexylmethoxy)methyl]-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, (12)5-{7-ethyl-4-(5-methyl-3-pyridinyl)-2-[(4-pyridinylmethoxy)methyl]pyrrolo[1,2-b]pyridazin-3-yl}pentanoicacid, (13) 4-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]butanoic acid, (14)5-[4-(5-chloro-3-pyridinyl)-7-ethyl-2-(methoxymethyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoicacid, or a pharmaceutically acceptable salt thereof.
 9. A process forpreparing a compound of claim 1 comprising (1) reacting a compound (II)of formula

wherein R³ and R⁴ are as defined in claim 1 or a salt thereof with acompound (III) of formula

wherein R¹ and R² are as defined in claim 1 or a salt thereof to obtaina compound (I) of formula

wherein R¹, R², R³, and R⁴ are as defined in claim 1 or a salt thereof,or (2) reacting a compound (V) of formula

wherein R⁴ is as defined in claim 1 or a salt thereof with a compound(VI) of formula

wherein R¹, R² and R³ are as defined in claim 1 or a salt thereof toobtain a compound (I) of formula

wherein R¹, R², R³ and R⁴ are as defined in claim 1 or a salt thereof.10. A pharmaceutical composition comprising: a compound of claim 1 inadmixture with a pharmaceutically acceptable carrier. 11-13. (canceled)14. A method for inhibiting the activity of PDE-IV in a subjectcomprising: administering an effective amount of the compound of claim 1to the subject to inhibit PDE-IV activity.
 15. A method for treating, ina subject, asthma, chronic obstructive pulmonary disease (COPD),fibrotic disease, acute and fulminant hepatitis, hepatic steatosis(alcoholic or non-alcoholic steatohepatitis), chronic (viral ornon-viral) hepatitis, hepatic cirrhosis, autoimmune hepatitis,autoimmune inflammatory bowel disease, atopic dermatitis, Alzheimer'sdiseases, or viral infection, the method comprising: administering atherapeutically effective amount, or a prophylactically effectiveamount, of the compound of claim 1 to the subject.
 16. (canceled)
 17. Amethod for inhibiting TNF synthesis in a subject, the method comprising:administering an effective amount of the compound of claim 1 to asubject to inhibit TNF synthesis.
 18. The compound of claim 1, whereinR⁷ is (1) a hydrogen, (2) a substituted aryl or an unsubstituted aryl,(3) a cyano, (4) an amino, a protected amino, a or mono- ordi(lower)alkylamino, or (5) a lower alkylthio, a lower alkylsulfinyl ora lower alkylsulfonyl.